A Glimpse into Dendrimers Integration in Cancer Imaging and Theranostics.

Cancer is a result of abnormal cell proliferation. This pathology is a serious health problem since it is a leading cause of death worldwide. Current anti-cancer therapies rely on surgery, radiation, and chemotherapy. However, these treatments still present major associated problems, namely the absence of specificity. Thus, it is urgent to develop novel therapeutic strategies. Nanoparticles, particularly dendrimers, have been paving their way to the front line of cancer treatment, mostly for drug and gene delivery, diagnosis, and disease monitoring. This is mainly derived from their high versatility, which results from their ability to undergo distinct surface functionalization, leading to improved performance. In recent years, the anticancer and antimetastatic capacities of dendrimers have been discovered, opening new frontiers to dendrimer-based chemotherapeutics. In the present review, we summarize the intrinsic anticancer activity of different dendrimers as well as their use as nanocarriers in cancer diagnostics and treatment.

Lipid Droplets in Cancer: From Composition and Role to Imaging and Therapeutics.

Cancer is the second most common cause of death worldwide, having its origin in the abnormal growth of cells. Available chemotherapeutics still present major drawbacks, usually associated with high toxicity and poor distribution, with only a small fraction of drugs reaching the tumour sites. Thus, it is urgent to develop novel therapeutic strategies. Cancer cells can reprogram their lipid metabolism to sustain uncontrolled proliferation, and, therefore, accumulate a higher amount of lipid droplets (LDs). LDs are cytoplasmic organelles that store neutral lipids and are hypothesized to sequester anti-cancer drugs, leading to reduced efficacy. Thus, the increased biogenesis of LDs in neoplastic conditions makes them suitable targets for anticancer therapy and for the development of new dyes for cancer cells imaging. In recent years, cancer nanotherapeutics offered some exciting possibilities, including improvement tumour detection and eradication. In this review we summarize LDs biogenesis, structure and composition, and highlight their role in cancer theranostics.

[Risk Factors Associated with the Refusal of Surgery Vouchers: The Case of Central Portugal]. / Fatores de Risco Associados à Recusa de Notas de Transferência e Vales Cirurgia: O Caso da Região Centro em Portugal.

INTRODUCTION: In Portugal, the rate of refusals regarding transfer between hospitals through surgery vouchers is high, which makes it difficult to meet maximum waiting times for elective surgeries. The objectives of this study are to examine how many vouchers were issued and refused between the third quarter of 2016 and the fourth quarter of 2019 and the risk factors associated with their refusal, in Central Portugal Material and Methods: Data was obtained in the database of cancelled vouchers and the waiting list for surgery on the 31st December 2019. Multiple logistic regression was used to investigate risk factors. RESULTS: The number of issued vouchers increased after 2018 and the rate of refusals has been above 55% since the 3rd quarter of 2018. Refusal was more likely for individuals aged 55 years or above (OR = 1.136; CI = 1.041 - 1.240; OR = 1.095; CI = 1.005 - 1.194; OR = 1.098; CI = 1.002 - 1.203, for the age bands 55 - 64, 65 - 74 and 75 - 84, respectively), for inpatient surgery when compared to ambulatory (OR = 2.498; CI = 2.343 - 2.663) and for Orthopaedics when compared to General Surgery (OR = 1.123; CI = 1.037 - 1.217). The odds of refusal also varied across hospitals (for example OR = 3.853; CI = 3.610 - 4.113; OR = 3.600; CI = 3.171 - 4.087; OR = 2.751; CI =3.383 - 3.175 e OR = 1.337; CI = 1.092 - 1.637, for hospitals identified as HO_2, HO_7, HO_4 and HO_6, respectively). CONCLUSION: In this study, we have confirmed that the number of issued surgery vouchers increased after the administrative reduction of maximum waiting times in 2018 and that the rate of transfer refusals has been increasing since 2016 and has remained above 55% from the third trimester of 2018 onwards. Some of the factors for which we obtained a positive association with refusal are age, inpatient surgery (compared to ambulatory) and Orthopaedics (compared to General Surgery).

Introdução: Em Portugal, a recusa de Notas de Transferência e Vales Cirurgia é elevada, dificultando o cumprimento dos tempos máximos de resposta garantidos para cirurgias eletivas. Os objetivos deste estudo foram analisar a evolução de notas e vales emitidos/recusados para o período compreendido entre o terceiro trimestre de 2016 e o quarto trimestre de 2019 e os fatores de risco associados à sua recusa, na Região Centro, em Portugal.Material e Métodos: Os dados provêm da base de dados de notas/vales cancelados e da lista de inscritos para cirurgia a 31 de dezembro de 2019. Na análise dos fatores de risco recorremos à regressão logística múltipla.Resultados: A emissão de notas/vales aumentou após 2018 e as taxas de recusa de transferência mantiveram-se acima dos 55% a partir do terceiro trimestre de 2018. A chance de recusa foi maior para idades superiores a 55 anos (OR = 1,136; IC = 1,041 ­ 1,240; OR = 1,095; IC = 1,005 ­ 1,194; OR = 1,098; IC = 1,002 ­ 1,203, para as faixas etárias 55 - 64, 65 - 74 e 75 - 84, respetivamente) para a cirurgia convencional, quando comparada com ambulatório (OR = 2,498; IC = 2,343 ­ 2,663) e para a especialidade de Ortopedia, quando comparada com Cirurgia Geral (OR = 1,123; IC = 1,037 ­ 1,217). A chance de recusa variou também entre hospitais (por exemplo OR = 3,853; IC = 3,610 ­ 4,113; OR = 3,600; IC = 3,171 ­ 4,087; OR = 2,751; IC = 3,383 ­ 3,175 e OR = 1,337; IC= 1,092 ­1,637, para os hospitais de origem identificados como HO_2, HO_7, HO_4 e HO_6, respetivamente).Conclusão: Neste estudo confirmou-se que a emissão de notas de transferência/vales cirurgia aumentou após a redução legal dos tempos máximos de resposta garantidos em 2018 e que as taxas de recusa de transferência vinham já a registar uma tendência de aumento desde 2016, tendo-se mantido acima dos 55% a partir do terceiro trimestre de 2018. Alguns fatores para os quais se encontrou uma associação positiva com a recusa são a idade, a cirurgia convencional (em comparação com ambulatório) e a especialidade de Ortopedia (em comparação com Cirurgia Geral).

The BASHY Platform Enables the Assembly of a Fluorescent Bortezomib-GV1001 Conjugate.

In this study, we show that fluorescent boronic-acid derived salicylidenehydrazone complexes (BASHY) can function as fluorescent linkers for bioconjugates that were used to monitor the delivery of the proteasome inhibitor bortezomib (Btz) to HT-29 cancer cells. BASHY complexes were structurally optimized to improve the stability of the complex in buffered conditions (ammonium acetate, pH 7 up to t 1/2 = 40 h), photophysically characterized regarding their fluorescence properties and used in confocal microscopy colocalization studies that revealed their intracellular sequestration by lipid droplets. The accumulation in these hydrophobic organelles limited the hydrolysis of the complex and consequently the drug release, a problem that was circumvented by the conjugation of the BASHY-Btz complex with a cell-penetrating peptide GV1001-C. The conjugate exhibited an improved cytoplasmic availability as confirmed by confocal fluorescence microscopy studies and an improved potency against HT-29 cancer cells (IC50 = 100 nM) as compared to the nontargeted complex (IC50 = 450 nM).

Performance of machine-learning algorithms to pattern recognition and classification of hearing impairment in Brazilian farmers exposed to pesticide and/or cigarette smoke.

The use of pesticides has been increasing in agriculture, leading to a public health problem. The aim of this study was to evaluate ototoxic effects in farmers who were exposed to cigarette smoke and/or pesticides and to identify possible classification patterns in the exposure groups. The sample included 127 participants of both sexes aged between 18 and 39, who were divided into the following four groups: control group (CG), smoking group (SG), pesticide group (PG), and smoking + pesticide group (SPG). Meatoscopy, pure tone audiometry, logoaudiometry, high-frequency thresholds, and immittance testing were performed. Data were evaluated by artificial neural network (ANN), K-nearest neighbors (K-NN), and support vector machine (SVM). There was symmetry between the right and left ears, an increase in the incidence of hearing loss at high frequency and of downward sloping audiometric curve configuration, and alteration of stapedial reflex in the three exposed groups. The machine-learning classifiers achieved good classification performance (control and exposed). The best classification results occur in high type (I and II) datasets (about 90% accuracy) in k-NN test. It is concluded that both xenobiotic substances have ototoxic potential; however, their combined use does not present additive or potentiating effects recognizable by the algorithms.

Evaluation of genotoxic effects in Brazilian agricultural workers exposed to pesticides and cigarette smoke using machine-learning algorithms.

Monitoring exposure to xenobiotics by biomarker analyses, such as a micronucleus assay, is extremely important for the precocious detection and prevention of diseases, such as oral cancer. The aim of this study was to evaluate genotoxic effects in rural workers who were exposed to cigarette smoke and/or pesticides and to identify possible classification patterns in the exposure groups. The sample included 120 participants of both sexes aged between 18 and 39, who were divided into the following four groups: control group (CG), smoking group (SG), pesticide group (PG), and smoking + pesticide group (SPG). Their oral mucosa cells were stained with Giemsa for cytogenetic analysis. The total numbers of nuclear abnormalities (CG = 27.16 ± 14.32, SG = 118.23 ± 74.78, PG = 184.23 ± 52.31, and SPG = 191.53 ± 66.94) and micronuclei (CG = 1.46 ± 1.40, SG = 12.20 ± 10.79, PG = 21.60 ± 8.24, and SPG = 20.26 ± 12.76) were higher (p < 0.05) in the three exposed groups compared to the GC. In this study, we considered several different classification algorithms (the artificial neural network, K-nearest neighbors, support vector machine, and optimum path forest). All of the algorithms displayed good classification (accuracy > 80%) when using dataset2 (without the redundant exposure type SPG). It is clear that the data form a robust pattern and that classifiers could be successfully trained on small datasets from the exposure groups. In conclusion, exposing agricultural workers to pesticides and/or tobacco had genotoxic potential, but concomitant exposure to xenobiotics did not lead to additive or potentiating effects.

Influence of different spacers on the biological profile of a DOTA-somatostatin analogue.

Radiolabeled somatostatin analogues have been successfully used for targeted radiotherapy and for imaging of somatostatin receptor (sst1-5)-positive tumors. Nevertheless, these analogues are subject to improving their tumor-to-nontarget ratio to enhance their diagnostic or therapeutic properties, preventing nephrotoxicity. In order to understand the influence of lipophilicity and charge on the pharmacokinetic profile of [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)]-somatostatin-based radioligands such as [DOTA,1-Nal3]-octreotide (DOTA-NOC), different spacers (X) based on 8-amino-3,6-dioxaoctanoic acid (PEG2), 15-amino-4,7,10,13-tetraoxapentadecanoic acid (PEG4), N-acetyl glucosamine (GlcNAc), triglycine, beta-alanine, aspartic acid, and lysine were introduced between the chelator DOTA and the peptide NOC. All DOTA-X-NOC conjugates were synthesized by Fmoc solid-phase synthesis. The partition coefficient (log D) at pH = 7.4 indicated that higher hydrophilicity than [111In-DOTA]-NOC was achieved with the introduction of the mentioned spacers, except with triglycine and beta-alanine. The high affinity of [InIII-DOTA]-NOC for human sst2 (hsst2) was preserved with the structural modifications, while an overall drop for hsst3 affinity was observed, except in the case of [InIII-DOTA]-beta-Ala-NOC. The new conjugates preserved the good affinity for hsst5, except for [InIII-DOTA]-Asn(GlcNAc)-NOC, which showed decreased affinity. A significant 1.2-fold improvement in the specific internalization rate in AR4-2J rat pancreatic tumor cells (sst2 receptor expression) at 4 h was achieved with the introduction of Asp as a spacer in the parent compound. In sst3-expressing HEK cells, the specific internalization rate at 4 h for [111In-DOTA]-NOC (13.1% +/- 0.3%) was maintained with [111In-DOTA]-beta-Ala-NOC (14.0% +/- 1.8%), but the remaining derivatives showed <2% specific internalization. Biodistribution studies were performed with Lewis rats bearing the AR4-2J rat pancreatic tumor. In comparison to [111In-DOTA]-NOC (2.96% +/- 0.48% IA/g), the specific uptake in the tumor at 4 h p.i. was significantly improved for the 111In-labeled sugar analogue (4.17% +/- 0.46% IA/g), which among all the new derivatives presented the best tumor-to-kidney ratio (1.9).

13- and 14-membered macrocyclic ligands containing methylcarboxylate or methylphosphonate pendant arms: chemical and biological evaluation of their (153)Sm and (166)Ho complexes as potential agents for therapy or bone pain palliation.

The stability constants of La(3+), Sm(3+) and Ho(3+) complexes with 13- and 14-membered macrocycles having methylcarboxylate (trita and teta) or methylphosphonate (tritp and tetp) arms were determined. All the ligands were labelled with (153)Sm and (166)Ho in order to evaluate the effect of the macrocyclic cavity size and type of appended arms on their in vitro and in vivo behaviour. The radiolabelling efficiency was found to be higher than 98% for all the complexes, except for those of tetp. All radiocomplexes studied are hydrophilic with an overall negative charge and low plasmatic protein binding. Good in vitro stability in physiological media and human serum was found for all complexes, except the (153)Sm/(166)Ho-teta, which are unstable in phosphate buffer (pH 7.4). In vitro hydroxyapatite (HA) adsorption studies indicated that (153)Sm/(166)Ho-tritp complexes bind to HA having the (166)Ho complex the highest degree of adsorption (>80%, 10 mg). Biodistribution studies in mice demonstrated that (153)Sm/(166)Ho-trita complexes have a fast tissue clearance with more than 95% of the injected activity excreted after 2 h, value that is comparable to the corresponding dota complexes. In contrast, the (153)Sm-teta complex has a significantly lower total excretion. (153)Sm/(166)Ho-tritp complexes are retained by the bone, particularly (166)Ho-tritp that has 5-6% (% I.D./g) bone uptake and also a high rate of total excretion. Thus, these studies support the potential interest of (153)Sm/(166)Ho-trita complexes for therapy when conjugated to a biomolecule and the potential usefulness of the (166)Ho-tritp complex in bone pain palliation.