A Step Forward for the Treatment of Localized Prostate Cancer Using Gold Nanoparticles Combined with Laser Irradiation.

Prostate cancer (PCA) is the second most common cancer diagnosis in men and the fifth leading cause of death worldwide. The conventional treatments available are beneficial to only a few patients and, in those, some present adverse side effects that eventually affect the quality of life of most patients. Thus, there is an urgent need for effective, less invasive and targeted specific treatments for PCA. Photothermal therapy (PTT) is a minimally invasive therapy that provides a localized effect for tumour cell ablation by activating photothermal agents (PTA) that mediate the conversion of the light beam's energy into heat at the site. As tumours are unable to easily dissipate heat, they become more susceptible to temperature increases. In the PTT field, gold nanoparticles (AuNPs) have been attracting interest as PTA. The aim of this study was to formulate AuNPs capable of remaining retained in the tumour and subsequently generating heat at the tumour site. AuNPs were synthesized and characterized in terms of size, polydispersity index (PdI), zeta potential (ZP), morphology and the surface plasmon resonance (SPR). The safety of AuNPs and their efficacy were assessed using in vitro models. A preliminary in vivo safety assessment of AuNPs with a mean size lower than 200 nm was confirmed. The morphology was spherical-like and the SPR band showed good absorbance at the laser wavelength. Without laser, AuNPs proved to be safe both in vitro (>70% viability) and in vivo. In addition, with laser irradiation, they proved to be relatively effective in PCA cells. Overall, the formulation appears to be promising for use in PTT.

An alternative hybrid lipid nanosystem combining cytotoxic and magnetic properties as a tool to potentiate antitumor effect of 5-fluorouracil.

AIMS: Colorectal cancer is the third most frequent type of cancer and the second leading cause of cancer-related deaths worldwide. The majority of cases are diagnosed at a later stage, leading to the need for more aggressive treatments such as chemotherapy. 5-Fluorouracil (5-FU), known for its high cytotoxic properties has emerged as a chemotherapeutic agent. However, it presents several drawbacks such as lack of specificity and short half-life. To reduce these drawbacks, several strategies have been designed namely chemical modification or association to drug delivery systems. MATERIALS AND METHODS: Current research was focused on the design, physicochemical characterization and in vitro evaluation of a lipid-based system loaded with 5-FU. Furthermore, aiming to maximize preferential targeting and release at tumour sites, a hybrid lipid-based system, combining both therapeutic and magnetic properties was developed and validated. For this purpose, liposomes co-loaded with 5-FU and iron oxide (II, III) nanoparticles were accomplished. KEY FINDINGS: The characterization of the developed nanoformulation was performed in terms of incorporation parameters, mean size and surface charge. In vitro studies assessed in a murine colon cancer cell line confirmed that 5-FU antiproliferative activity was preserved after incorporation in liposomes. In same model, iron oxide (II, III) nanoparticles did not exhibit cytotoxic properties. Additionally, the presence of these nanoparticles was shown to confer magnetic properties to the liposomes, allowing them to respond to external magnetic fields. SIGNIFICANCE: Overall, a lipid nanosystem loading a chemotherapeutic agent displaying magnetic characteristics was successfully designed and physicochemically characterized, for further in vivo applications.

Rational approach to design gold nanoparticles for photothermal therapy: the effect of gold salt on physicochemical, optical and biological properties.

Among the unique characteristics associated to gold nanoparticles (AuNPs) in biomedicine, their ability to convert light energy into heat opens ventures for improved cancer therapeutic options, such as photothermal therapy (PTT). PTT relies on the local hyperthermia of tumor cells upon irradiation with light beams, and the association of AuNPs with radiation within the near infrared (NIR) range constitutes an advantageous strategy to potentially improve PTT efficacy. Herein, it was explored the effect of the gold salt on the AuNPs' physicochemical and optical properties. Mostly spherical-like negatively charged AuNPs with variable sizes and absorbance spectra were obtained. In addition, photothermal features were assessed using in vitro phantom models. The best formulation showed the ability to increase their temperature in aqueous solution up to 19 °C when irradiated with a NIR laser for 20 min. Moreover, scanning transmission electron microscopy confirmed the rearrangement of the gold atoms in a face-centered cubic structure, which further allowed to calculate the photothermal conversion efficiency upon combination of theoretical and experimental data. AuNPs also showed local retention after being locally administered in in vivo models. These last results obtained by computerized tomography allow to consider these AuNPs as promising elements for a PTT system. Moreover, AuNPs showed high potential for PTT by resulting in in vitro cancer cells' viability reductions superior to 70 % once combine with 5 min of NIR irradiation.

Nanoparticle-Based Treatment in Glioblastoma.

Glioblastoma (GB) is a malignant glioma associated with a mean overall survival of 12 to 18 months, even with optimal treatment, due to its high relapse rate and treatment resistance. The standardized first-line treatment consists of surgery, which allows for diagnosis and cytoreduction, followed by stereotactic fractionated radiotherapy and chemotherapy. Treatment failure can result from the poor passage of drugs through the blood-brain barrier (BBB). The development of novel and more effective therapeutic approaches is paramount to increasing the life expectancy of GB patients. Nanoparticle-based treatments include epitopes that are designed to interact with specialized transport systems, ultimately allowing the crossing of the BBB, increasing therapeutic efficacy, and reducing systemic toxicity and drug degradation. Polymeric nanoparticles have shown promising results in terms of precisely directing drugs to the brain with minimal systemic side effects. Various methods of drug delivery that pass through the BBB, such as the stereotactic injection of nanoparticles, are being actively tested in vitro and in vivo in animal models. A significant variety of pre-clinical studies with polymeric nanoparticles for the treatment of GB are being conducted, with only a few nanoparticle-based drug delivery systems to date having entered clinical trials. Pre-clinical studies are key to testing the safety and efficacy of these novel anticancer therapies and will hopefully facilitate the testing of the clinical validity of this promising treatment method. Here we review the recent literature concerning the most frequently reported types of nanoparticles for the treatment of GB.

Cu(II) and Zn(II) Complexes of New 8-Hydroxyquinoline Schiff Bases: Investigating Their Structure, Solution Speciation, and Anticancer Potential.

We report the synthesis and characterization of three novel Schiff bases (L1-L3) derived from the condensation of 2-carbaldehyde-8-hydroxyquinoline with amines containing morpholine or piperidine moieties. These were reacted with CuCl2 and ZnCl2 yielding six new coordination compounds, with the general formula ML2, where M = Cu(II) or Zn(II) and L = L1-L3, which were all characterized by analytical, spectroscopic (Fourier transform infrared (FTIR), UV-visible absorption, nuclear magnetic resonance (NMR), or electron paramagnetic resonance (EPR)), and mass spectrometric techniques, as well as by single-crystal X-ray diffraction. In the solid state, two Cu(II) complexes, with L1 and L2, are obtained as dinuclear compounds, with relatively short Cu-Cu distances (3.146 and 3.171 Å for Cu2(L1)4 and Cu2(L2)4, respectively). The free ligands show moderate lipophilicity, while their complexes are more lipophilic. The pKa values of L1-L3 and formation constants of the complex (for ML and ML2) species were determined by spectrophotometric titrations, with the Cu(II) complexes showing higher stability than the Zn(II) complexes. EPR indicated the presence of several species in solution as pH varied and binding modes were proposed. The binding of the complexes to bovine serum albumin (BSA) was evaluated by fluorescence and circular dichroism (CD) spectroscopies. All complexes bind BSA, and as demonstrated by CD, the process takes several hours to reach equilibrium. The antiproliferative activity was evaluated in malignant melanoma cells (A375) and in noncancerous keratinocytes (HaCaT). All complexes display significant cytotoxicity (IC50 < 10 µM) but modest selectivity. The complexes show higher activity than the free ligands, the Cu(II) complexes being more active than the Zn(II) complexes, and approximately twice more cytotoxic than cisplatin. A Guava ViaCount assay corroborated the antiproliferative activity.

The current role of cannabis and cannabinoids in health: A comprehensive review of their therapeutic potential.

There has been an increased interest of the scientific community in cannabis and its constituents for therapeutic purposes. Although it is believed that cannabinoids can be effective for a few different conditions and syndromes, there are little objective data that clearly support the use of cannabis, cannabis extracts or even cannabidiol (CBD) oil. This review aims to explore the therapeutic potential of phytocannabinoids and synthetic cannabinoids for the treatment of several diseases. A broad search covering the past five years, was performed in PubMed and ClinicalTrial.gov databases, to identify papers focusing on the use of medical phytocannabinoids in terms of tolerability, efficacy and safety. Accordingly, there are preclinical data supporting the use of phytocannabinoids and synthetic cannabinoids for the management of neurological pathologies, acute and chronical pain, cancer, psychiatric disorders and chemotherapy-induced emetic symptoms. However, regarding the clinical trials, most of the collected data do not fully support the use of cannabinoids in the treatment of such conditions. Consequently, more studies are still needed to clarify ascertain if the use of these compounds is useful in the management of different pathologies.

Experimental Murine Models for Colorectal Cancer Research.

Colorectal cancer (CRC) is the third most prevalent malignancy worldwide and in both sexes. Numerous animal models for CRC have been established to study its biology, namely carcinogen-induced models (CIMs) and genetically engineered mouse models (GEMMs). CIMs are valuable for assessing colitis-related carcinogenesis and studying chemoprevention. On the other hand, CRC GEMMs have proven to be useful for evaluating the tumor microenvironment and systemic immune responses, which have contributed to the discovery of novel therapeutic approaches. Although metastatic disease can be induced by orthotopic injection of CRC cell lines, the resulting models are not representative of the full genetic diversity of the disease due to the limited number of cell lines suitable for this purpose. On the other hand, patient-derived xenografts (PDX) are the most reliable for preclinical drug development due to their ability to retain pathological and molecular characteristics. In this review, the authors discuss the various murine CRC models with a focus on their clinical relevance, benefits, and drawbacks. From all models discussed, murine CRC models will continue to be an important tool in advancing our understanding and treatment of this disease, but additional research is required to find a model that can correctly reflect the pathophysiology of CRC.

Safety of Gold Nanoparticles: From In Vitro to In Vivo Testing Array Checklist.

In recent years, gold nanoparticles (AuNPs) have aroused the interest of many researchers due to their unique physicochemical and optical properties. AuNPs are being explored in a variety of biomedical fields, either in diagnostics or therapy, particularly for localized thermal ablation of cancer cells after light irradiation. Besides the promising therapeutic potential of AuNPs, their safety constitutes a highly important issue for any medicine or medical device. For this reason, in the present work, the production and characterization of physicochemical properties and morphology of AuNPs coated with two different materials (hyaluronic and oleic acids (HAOA) and bovine serum albumin (BSA)) were firstly performed. Based on the above importantly referred issue, the in vitro safety of developed AuNPs was evaluated in healthy keratinocytes, human melanoma, breast, pancreatic and glioblastoma cancer cells, as well as in a three-dimensional human skin model. Ex vivo and in vivo biosafety assays using, respectively, human red blood cells and Artemia salina were also carried out. HAOA-AuNPs were selected for in vivo acute toxicity and biodistribution studies in healthy Balb/c mice. Histopathological analysis showed no significant signs of toxicity for the tested formulations. Overall, several techniques were developed in order to characterize the AuNPs and evaluate their safety. All these results support their use for biomedical applications.

The sFlt1/PlGF ratio predicts faster fetal deterioration in early fetal growth restriction: A historical cohort study.

INTRODUCTION: The velocity of fetal deterioration in fetal growth restriction is extremely variable, which makes monitoring and counseling very challenging. The soluble fms-like tyrosine kinase to placental growth factor (sFlt1/PlGF) ratio provides a readout of the vasoactive environment that correlates with preeclampsia and fetal growth restriction and that could be useful to predict fetal deterioration. Previous studies showed a correlation between higher sFlt1/PlGF ratios and lower gestational ages at birth, although it is unclear whether this is due to the increased incidence of preeclampsia. Our goal was to evaluate whether the sFlt1/PlGF ratio predicts faster fetal deterioration in early fetal growth restriction. MATERIAL AND METHODS: This was a historical cohort study in a tertiary maternity hospital. Data from singleton pregnancies with early fetal growth restriction (diagnosed before 32 gestational weeks) confirmed after birth monitored between January 2016 and December 2020 were retrieved from clinical files. Cases of chromosomal/fetal abnormalities, infection and medical terminations of pregnancy were excluded. The sFlt1/PlGF ratio was acquired at diagnosis of early fetal growth restriction in our unit. The correlation of log10 sFlt1/PlGF with latency to delivery/fetal demise was assessed with linear, logistic (positive sFlt1/PlGF if >85) and Cox regression excluding deliveries for maternal conditions and controlling for preeclampsia, gestational age at time of ratio test, maternal age and smoking during pregnancy. Receiver-operating characteristic (ROC) analysis tested the performance of sFlt1/PlGF ratio in predicting delivery for fetal reasons in the following week. RESULTS: 125 patients were included. Mean sFlt1/PlGF ratio was 91.2 (SD 148.7) and 28% of patients had a positive ratio. A higher log10 sFlt1/PlGF ratio predicted shorter latency for delivery/fetal demise in linear regression after controlling for confounders, ß = -3.001, (-3.713 to -2.288). Logistic regression with ratio positivity confirmed these findings (latency for delivery 5.7 ± 3.32 weeks for ratios ≤85 vs 1.9 ± 1.52 weeks for ratios >85); ß = -0.698 (-1.064 to -0.332). Adjusted Cox regression showed that a positive ratio confers a significantly positive hazard ratio (HR) for earlier delivery/fetal demise, HR 9.869 (5.061-19.243). ROC analysis showed an area under the curve of 0.847 (SE ± 0.06). CONCLUSIONS: sFlt1/PlGF ratio is correlated with faster fetal deterioration in early fetal growth restriction, independently of preeclampsia.

Highlighted Advances in Therapies for Difficult-To-Treat Brain Tumours Such as Glioblastoma.

Glioblastoma multiforme (GBM) remains a challenging disease, as it is the most common and deadly brain tumour in adults and has no curative solution and an overall short survival time. This incurability and short survival time means that, despite its rarity (average incidence of 3.2 per 100,000 persons), there has been an increased effort to try to treat this disease. Standard of care in newly diagnosed glioblastoma is maximal tumour resection followed by initial concomitant radiotherapy and temozolomide (TMZ) and then further chemotherapy with TMZ. Imaging techniques are key not only to diagnose the extent of the affected tissue but also for surgery planning and even for intraoperative use. Eligible patients may combine TMZ with tumour treating fields (TTF) therapy, which delivers low-intensity and intermediate-frequency electric fields to arrest tumour growth. Nonetheless, the blood-brain barrier (BBB) and systemic side effects are obstacles to successful chemotherapy in GBM; thus, more targeted, custom therapies such as immunotherapy and nanotechnological drug delivery systems have been undergoing research with varying degrees of success. This review proposes an overview of the pathophysiology, possible treatments, and the most (not all) representative examples of the latest advancements.

Current Insights and Progress in the Clinical Management of Head and Neck Cancer.

Head and neck cancer (HNC), also known as the cancer that can affect the structures between the dura mater and the pleura, is the 6th most common type of cancer. This heterogeneous group of malignancies is usually treated with a combination of surgery and radio- and chemotherapy, depending on if the disease is localized or at an advanced stage. However, most HNC patients are diagnosed at an advanced stage, resulting in the death of half of these patients. Thus, the prognosis of advanced or recurrent/metastatic HNC, especially HNC squamous cell carcinoma (HNSCC), is notably poorer than the prognosis of patients diagnosed with localized HNC. This review explores the epidemiology and etiologic factors of HNC, the histopathology of this heterogeneous cancer, and the diagnosis methods and treatment approaches currently available. Moreover, special interest is given to the novel therapies used to treat HNC subtypes with worse prognosis, exploring immunotherapies and targeted/multi-targeted drugs undergoing clinical trials, as well as light-based therapies (i.e., photodynamic and photothermal therapies).

Metal Coordination and Biological Screening of a Schiff Base Derived from 8-Hydroxyquinoline and Benzothiazole.

Designing new metallodrugs for anticancer therapy is a driving force in the scientific community. Aiming to contribute to this field, we hereby report the development of a Schiff base (H2L) derived from the condensation of 2-carbaldehyde-8-hydroxyquinoline with 2-hydrazinobenzothiazole and its complexation with transition metal ions. All compounds were characterised by analytical and spectroscopic techniques, which disclosed their structure: [Cu(HL)Cl], [Cu(HL)2], [Ni(HL)(acetate)], [Ni(HL)2], [Ru(HL)Cl(DMSO)], [VO(HL)2] and [Fe(HL)2Cl(H2O)]. Different binding modes were proposed, showing the ligand's coordination versatility. The ligand proton dissociation constants were determined, and the tested compounds showed high lipophilicity and light sensitivity. The stability of all complexes in aqueous media and their ability to bind to albumin were screened. Based on an antiproliferative in vitro screening, [Ni(HL)(acetate)] and [Ru(HL)Cl(DMSO)] were selected for further studies aiming to investigate their mechanisms of action and therapeutic potential towards colon cancer. The complexes displayed IC50 < 21 µM towards murine (CT-26) and human (HCT-116) colon cancer cell lines. Importantly, both complexes exhibited superior antiproliferative properties compared to the clinically approved 5-fluorouracil. [Ni(HL)(acetate)] induced cell cycle arrest in S phase in CT-26 cells. For [Ru(HL)Cl(DMSO)] this effect was observed in both colon cancer cell lines. Additionally, both compounds significantly inhibited cell migration particularly in the human colon cancer cell line, HCT-116. Overall, the therapeutic potential of both metal complexes was demonstrated.

Melanoma Management: From Epidemiology to Treatment and Latest Advances.

Melanoma is the deadliest skin cancer, whose morbidity and mortality indicators show an increasing trend worldwide. In addition to its great heterogeneity, melanoma has a high metastatic potential, resulting in very limited response to therapies currently available, which were restricted to surgery, radiotherapy and chemotherapy for many years. Advances in knowledge about the pathophysiological mechanisms of the disease have allowed the development of new therapeutic classes, such as immune checkpoint and small molecule kinase inhibitors. However, despite the incontestable progress in the quality of life and survival rates of the patients, effectiveness is still far from desired. Some adverse side effects and resistance mechanisms are the main barriers. Thus, the search for better options has resulted in many clinical trials that are now investigating new drugs and/or combinations. The low water solubility of drugs, low stability and rapid metabolism limit the clinical potential and therapeutic use of some compounds. Thus, the research of nanotechnology-based strategies is being explored as the basis for the broad application of different types of nanosystems in the treatment of melanoma. Future development focus on challenges understanding the mechanisms that make these nanosystems more effective.

How to Treat Melanoma? The Current Status of Innovative Nanotechnological Strategies and the Role of Minimally Invasive Approaches like PTT and PDT.

Melanoma is the most aggressive type of skin cancer, the incidence and mortality of which are increasing worldwide. Its extensive degree of heterogeneity has limited its response to existing therapies. For many years the therapeutic strategies were limited to surgery, radiotherapy, and chemotherapy. Fortunately, advances in knowledge have allowed the development of new therapeutic strategies. Despite the undoubted progress, alternative therapies are still under research. In this context, nanotechnology is also positioned as a strong and promising tool to develop nanosystems that act as drug carriers and/or light absorbents to potentially improve photothermal and photodynamic therapies outcomes. This review describes the latest advances in nanotechnology field in the treatment of melanoma from 2011 to 2022. The challenges in the translation of nanotechnology-based therapies to clinical applications are also discussed. To sum up, great progress has been made in the field of nanotechnology-based therapies, and our understanding in this field has greatly improved. Although few therapies based on nanoparticulate systems have advanced to clinical trials, it is expected that a large number will come into clinical use in the near future. With its high sensitivity, specificity, and multiplexed measurement capacity, it provides great opportunities to improve melanoma treatment, which will ultimately lead to enhanced patient survival rates.

Biological Thermal Performance of Organic and Inorganic Aerogels as Patches for Photothermal Therapy.

Aerogels are materials with unique properties, among which are low density and thermal conductivity. They are also known for their exquisite biocompatibility and biodegradability. All these features make them attractive for biomedical applications, such as their potential use in photothermal therapy (PTT). This technique is, yet, still associated with undesirable effects on surrounding tissues which emphasizes the need to minimize the exposure of healthy regions. One way to do so relies on the use of materials able to block the radiation and the heat generated. Aerogels might be potentially useful for this purpose by acting as insulators. Silica- and pectin-based aerogels are reported as the best inorganic and organic thermal insulators, respectively; thus, the aim of this work relies on assessing the possibility of using these materials as light and thermal insulators and delimiters for PTT. Silica- and pectin-based aerogels were prepared and fully characterized. The thermal protection efficacy of the aerogels when irradiated with a near-infrared laser was assessed using phantoms and ex vivo grafts. Lastly, safety was assessed in human volunteers. Both types presented good textural properties and safe profiles. Moreover, thermal activation unveils the better performance of silica-based aerogels, confirming the potential of this material for PTT.

Liposomal Formulations of a New Zinc(II) Complex Exhibiting High Therapeutic Potential in a Murine Colon Cancer Model.

Colorectal cancer is the second leading cause of cancer-related mortality. Many current therapies rely on chemotherapeutic agents with poor specificity for tumor cells. The clinical success of cisplatin has prompted the research and design of a huge number of metal-based complexes as potential chemotherapeutic agents. In this study, two zinc(II) complexes, [ZnL2] and [ZnL(AcO)], where AcO is acetate and L is an organic compound combining 8-hydroxyquinoline and a benzothiazole moiety, were developed and characterized. Analytical and spectroscopic studies, namely, NMR, FTIR, and UV-Vis allowed us to establish the complexes' structures, demonstrating the ligand-binding versatility: tetradentate in [ZnL(AcO)] and bidentate in [ZnL2]. Complexes were screened in vitro using murine and human colon cancer cells cultured in 2D and 3D settings. In 2D cells, the IC50 values were <22 µM, while in 3D settings, much higher concentrations were required. [ZnL(AcO)] displayed more suitable antiproliferative properties than [ZnL2] and was chosen for further studies. Moreover, based on the weak selectivity of the zinc-based complex towards cancer cell lines in comparison to the non-tumorigenic cell line, its incorporation in long-blood-circulating liposomes was performed, aiming to improve its targetability. The resultant optimized liposomal nanoformulation presented an I.E. of 76% with a mean size under 130 nm and a neutral surface charge and released the metal complex in a pH-dependent manner. The antiproliferative properties of [ZnL(AcO)] were maintained after liposomal incorporation. Preliminary safety assays were carried out through hemolytic activity that never surpassed 2% for the free and liposomal forms of [ZnL(AcO)]. Finally, in a syngeneic murine colon cancer mouse model, while free [ZnL(AcO)] was not able to impair tumor progression, the respective liposomal nanoformulation was able to reduce the relative tumor volume in the same manner as the positive control 5-fluorouracil but, most importantly, using a dosage that was 3-fold lower. Overall, our results show that liposomes were able to solve the solubility issues of the new metal-based complex and target it to tumor sites.

New iron(III) anti-cancer aminobisphenolate/phenanthroline complexes: Enhancing their therapeutic potential using nanoliposomes.

Malignant melanoma is an aggressive and deadly form of skin cancer and novel and improved therapeutic options are needed. A promising strategy involves the use of metallodrugs combined with liposomes for targeted delivery to cancer cells. In this work, a family of iron(III) complexes was synthesized bearing a trianionic aminobisphenolate ligand (L) and phenanthroline-type co-ligands (NN). Four ternary iron complexes of general formula [Fe(L)(NN)] were obtained: [Fe(L)(amphen)] (1), [Fe(L)(phen)] (2), [Fe(L)(Clphen)] (3), and [Fe(L)(Mephen)] (4), as well as a fifth complex [Fe(L)(NEt3)(H2O)] (5) without the bidentate co-ligand. All complexes were characterized by analytic and spectroscopic techniques and demonstrated to be stable in aqueous environment. Complexes 1 and 2 were able to bind DNA and presented high cytotoxic activity towards human cancer cells. Complex 1 (IronC) was selected for incorporation into different liposomal formulations, which were fully characterized and screened against murine melanoma cells. The IronC liposomal formulation with the highest incorporation efficiency (∼95%) and a low IC50 value (7.1 ± 0.7 µM) was selected for in vivo evaluation. In a syngeneic murine melanoma model the liposomal formulation of IronC yielded the highest impairment on tumour progression when compared with the control, temozolomide, and with the iron complex in free form.

The Role of Rosmarinic Acid on the Bioproduction of Gold Nanoparticles as Part of a Photothermal Approach for Breast Cancer Treatment.

Breast cancer is a high-burden malignancy for society, whose impact boosts a continuous search for novel diagnostic and therapeutic tools. Among the recent therapeutic approaches, photothermal therapy (PTT), which causes tumor cell death by hyperthermia after being irradiated with a light source, represents a high-potential strategy. Furthermore, the effectiveness of PTT can be improved by combining near infrared (NIR) irradiation with gold nanoparticles (AuNPs) as photothermal enhancers. Herein, an alternative synthetic method using rosmarinic acid (RA) for synthesizing AuNPs is reported. The RA concentration was varied and its impact on the AuNPs physicochemical and optical features was assessed. Results showed that RA concentration plays an active role on AuNPs features, allowing the optimization of mean size and maximum absorbance peak. Moreover, the synthetic method explored here allowed us to obtain negatively charged AuNPs with sizes favoring the local particle accumulation at tumor site and maximum absorbance peaks within the NIR region. In addition, AuNPs were safe both in vitro and in vivo. In conclusion, the synthesized AuNPs present favorable properties to be applied as part of a PTT system combining AuNPs with a NIR laser for the treatment of breast cancer.

The fetal origins of disease: a prospective cohort study on the association of preeclampsia and childhood obesity.

Cardiovascular diseases are the main cause of mortality worldwide, and childhood excess weight/obesity are strong correlators of accumulated risk in later life. A relationship between maternal preeclampsia and offspring's childhood obesity is recognized, but most studies fail to control for strong confounders. Our goal is to analyze the association between preeclampsia and childhood excess weight/obesity, after accounting for important confounders. We recruited 5133 women with singleton pregnancies during admission for delivery. Sixty-seven pregnancies were complicated by preeclampsia. Maternal and children outcomes were assessed at 10 years of age. We analyzed the association between preeclampsia and childhood excess weight/obesity by fitting a linear regression model (using offspring body mass index (BMI) z-score at 10 years of age) and a logistic regression model (using excess weight/obesity status). We then controlled both models for known confounders, namely maternal prepregnancy BMI, parity, and smoking during pregnancy. At 10 years of age, offspring of preeclamptic mothers had a higher BMI z-score and were more likely classified as overweight/obese, but these differences were not statistically significant. After controlling for maternal prepregnancy BMI, parity, and smoking during pregnancy, there was a high magnitude change in the beta coefficient of preeclampsia in the linear (0.175; -0.014) and the logistic regression models (1.48; 1.23) suggesting that the association between preeclampsia and childhood excess weigh/obesity is significantly confounded by these variables. These confounders also showed a significant association with childhood obesity. This finding suggests that in utero exposure to preeclampsia seems to have less impact in childhood obesity than the previously described confounders.

Prediction models of low-power holmium laser effectiveness in renal stone lithotripsy during retrograde intrarenal surgery.

The objectives of this study are to develop prediction models for total laser energy (TLE) in order to infer surgical time and assist operative planning of intrarenal low-power Ho:YAG laser lithotripsy, and to predict the fragmented volume as well as the stone-free status (SFS). A retrospective review was performed, comprising all single surgeon standardized retrograde intrarenal surgery and low-power Ho:YAG laser lithotripsy at a tertiary care centre between October 2014 and September 2019. Automated measurement of stone volume and stone density (MSD), measured in Hounsfield units (HU), was employed in both pre- and post-operative non-contrast-enhanced computed tomography (NCCT), using a standardized technique on Osirix Lite® software. SFS was defined as complete absence of stone fragments, or fragments < 0.1 cm on meticulous inspection at the end of the procedure, and residual stone burden < 0.0005 cm3 on postoperative NCCT at 3 months. Statistical analysis was performed using the STATA® version 13.1 software for regression models. A p value < .05 was considered statistically significant. A total of 100 patients met the inclusion criteria, requiring a median of 22.3 kJ/cm3 (13.4-36.0) and resulting in a SFS of 41% at 3 months. In a multivariate analysis, according to stone composition, predicted TLE is equal: for uric acid (UA), 11.17 × volume(cm3) + 0.17 × MSD(HU) + 7.48 kJ; for mixed stones, 11.17 × volume(cm3) + 0.17 × MSD(HU) + 6.26 kJ; for calcium oxalate monohydrate (CaOM) stones, 11.17 × volume(cm3) + 0.17 × MSD(HU) + 1.14 kJ; and for calcium phosphate (CaPh) stones 11.17 × volume(cm3) + 0.17 × MSD(HU) - 1.94 kJ. Predicted fragmented volume is equal to 0.93 × volume(cm3) cm3. The significant predictors for SFS were UA stones, the presence of multiple stones, and lower TLE. In clinical practice, our models for intrarenal low-power Ho:YAG laser lithotripsy indicate that larger, denser, and UA stones are associated to higher TLE, and that single and UA stones are more commonly associated to SFS. Since higher TLE means longer operative time, when adjusting for laser parameters, our prediction models may help urologists plan surgeries more precisely based on stone characteristics, ultimately optimizing patients' treatment.