Development and Psychometric Validation of the Breast Cancer Stigma Assessment Scale for Women with Breast Cancer and Its Survivors.

BACKGROUND: The increase in breast cancer cases and breast cancer survival makes it advisable to quantify the impact of the health-related stigma of this disease. PURPOSE/OBJECTIVES: To develop and validate a breast cancer stigma scale in Spanish. METHODS: Women diagnosed with, or survivors of, breast cancer were included. The development of the Breast Cancer Stigma Assessment Scale (BCSAS) involved both a literature review and personal interviews. Content validity was assessed using a Delphi study and a pilot test; construct validity was evaluated using an exploratory factor analysis; and convergent validity was assessed using six scales. Cronbach's α internal consistency and test-retest reliability were used to determine the reliability of the scales. RESULTS: 231 women responded to the 28-item scale. The BCSAS showed good reliability, with α = 0.897. Seven factors emerged: concealment (α = 0.765), disturbance (α = 0.772), internalized stigma (α = 0.750), aesthetics (α = 0.779), course (α = 0.599), danger (α = 0.502), and origin (α = 0.350). The test-retest reliability was 0.830 (p < 0.001). Significant correlation was observed with event centrality (r = 0.701), anxiety-depression (r = 0.668), shame (r = 0.645), guilt (r = 0.524), and quality of life (r = -0.545). CONCLUSIONS: The BCSAS is a reliable and valid measure of stigma in women with breast cancer and its survivors. It could be useful for detecting stigma risk and establishing psychotherapeutic and care priorities.

Structure-Based Optimization of Carbendazim-Derived Tubulin Polymerization Inhibitors through Alchemical Free Energy Calculations.

Carbendazim derivatives, commonly used as antiparasitic drugs, have shown potential as anticancer agents due to their ability to induce cell cycle arrest and apoptosis in human cancer cells by inhibiting tubulin polymerization. Crystallographic structures of α/ß-tubulin multimers complexed with nocodazole and mebendazole, two carbendazim derivatives with potent anticancer activity, highlighted the possibility of designing compounds that occupy both benzimidazole- and colchicine-binding sites. In addition, previous studies have demonstrated that the incorporation of a phenoxy group at position 5/6 of carbendazim increases the antiproliferative activity in cancer cell lines. Despite the significant progress made in identifying new tubulin-targeting anticancer compounds, further modifications are needed to enhance their potency and safety. In this study, we explored the impact of modifying the phenoxy substitution pattern on antiproliferative activity. Alchemical free energy calculations were used to predict the binding free energy difference upon ligand modification and define the most viable path for structure optimization. Based on these calculations, seven compounds were synthesized and evaluated against lung and colon cancer cell lines. Our results showed that compound 5a, which incorporates an α-naphthyloxy substitution, exhibits the highest antiproliferative activity against both cancer lines (SK-LU-1 and SW620, IC50 < 100 nM) and induces morphological changes in the cells associated with mitotic arrest and mitotic catastrophe. Nevertheless, the tubulin polymerization assay showed that 5a has a lower inhibitory potency than nocodazole. Molecular dynamics simulations suggested that this low antitubulin activity could be associated with the loss of the key H-bond interaction with V236. This study provides insights into the design of novel carbendazim derivatives with anticancer activity.

SHP2 promotes sarcoidosis severity by inhibiting SKP2-targeted ubiquitination of TBET in CD8+ T cells.

Sarcoidosis is an interstitial lung disease (ILD) characterized by interferon-γ (IFN-γ) and T-box expressed in T cells (TBET) dysregulation. Although one-third of patients progress from granulomatous inflammation to severe lung damage, the molecular mechanisms underlying this process remain unclear. Here, we found that pharmacological inhibition of phosphorylated SH2-containing protein tyrosine phosphatase-2 (pSHP2), a facilitator of aberrant IFN-γ abundance, decreased large granuloma formation and macrophage infiltration in the lungs of mice with sarcoidosis-like disease. Positive treatment outcomes were dependent on the effective enhancement of TBET ubiquitination within CD8+ T cells. Mechanistically, we identified a posttranslational modification pathway in which the E3 F-box protein S-phase kinase-associated protein 2 (SKP2) targets TBET for ubiquitination in T cells under normal conditions. However, this pathway was disrupted by aberrant pSHP2 signaling in CD8+ T cells from patients with progressive pulmonary sarcoidosis and end-stage disease. Ex vivo inhibition of pSHP2 in CD8+ T cells from patients with end-stage sarcoidosis enhanced TBET ubiquitination and suppressed IFN-γ and collagen synthesis. Therefore, these studies provided new mechanistic insights into the SHP2-dependent posttranslational regulation of TBET and identified SHP2 inhibition as a potential therapeutic intervention against severe sarcoidosis. Furthermore, these studies also suggest that the small-molecule SHP2 inhibitor SHP099 might be used as a therapeutic measure against human diseases linked to TBET or ubiquitination.

Development and Pharmacokinetic Evaluation of Two Parenteral Formulations of Albendazole Using Prodrug and Cosolvent Approaches.

Albendazole is a broad-spectrum anthelmintic drug used for parasitic infections. In addition, due to its mechanism of action, it has been studied as an anticancer agent. However, poor and highly variable bioavailability are limiting factors for its use in systemic illnesses. The present study aimed to develop two parenteral formulations of albendazole and to compare its pharmacokinetic profile with the conventional oral administration. Parenteral formulations were developed using two different approaches: a phosphonooxymethylated prodrug and cosolvents. For the albendazole prodrug, once synthetized, its solubility and hydrolysis with alkaline phosphatase were evaluated. A factorial design of experiments was used for the cosolvent formulation. Stability and hemolytic activity were assessed. A pharmacokinetic study was performed on New Zealand rabbits. Both formulations were administered intravenously, and the prodrug was also administered intramuscularly. Results were compared with those obtained after the oral administration of albendazole. A 20,000-fold and 6000-fold increase in albendazole solubility was found with the prodrug and cosolvent formulations, respectively. Both parenteral formulations displayed higher albendazole plasma concentrations for the first 2 h compared with oral administration, even when the oral dose was doubled. The absolute bioavailability of oral albendazole was 15.5% while for the intramuscular administration of the prodrug was 102.6%. Both parenteral formulations showed a significant decrease in the formation of albendazole sulfoxide (ANOVA p<0.05) and allowed greater exposure to albendazole. Albendazole cosolvent parenteral formulation could be a promising option in systemic illnesses considering its ease of preparation and superb pharmacokinetic performance.

Longitudinal study of the body mass index and biochemical nutritional parameters of patients in dialysis / Estudio longitudinal del índice de masa corporal y parámetros bioquímicos nutricionales en pacientes en diálisis

ABSTRACT Background/Aim: Chronic kidney failure is frequently related to malnutrition. This research aimed to assess the nutritional status of hemodialysis patients by assessing their biochemical and anthropometric parameters and determining whether the disorders suffered stemmed from nutritional deterioration directly related to time on dialysis. Materials and Methods: This research monitored 90 patients of both genders with chronic kidney failure who regularly received hemodialysis at the kidney unit of our Hospital in Granada (Spain) over five years. The patient's blood was tested quarterly for plasma albumin (Alb), total cholesterol (TC), and total proteins (TP) and monthly for transferrin (Tr). Anthropometric measurements were taken of the patient's weight, height, and body mass index (BMI) and, based on the patient's BMI, classified as established by the World Health Organization. Results: During the five years of our study, patients experienced a statistically significant decrease in total protein (0.941g/dl), plasma albumin (0.9382g/dl), total cholesterol (23.77mg/dl), and transferrin (78.17. g/dl) p < 0.0001. On the contrary, the mean BMI values did not show statistically relevant differences (p < 0.805). However, all patients remained in the WHO category of overweight. The body volume values did not show statistically significant differences either. Conclusions: In conclusion, the nutritional deterioration of these patients was not reflected in their BMI but mainly in their serum chemistry.

RESUMEN Antecedentes/Objetivo: La insuficiencia renal crónica está relacionada frecuentemente con la malnutrición, afectando aproximadamente a un tercio de los pacientes con enfermedad renal avanzada, lo que contribuye a su morbilidad y mortalidad. El objetivo de esta investigación fue evaluar el estado nutricional de los pacientes en hemodiálisis valorando sus parámetros bioquímicos y antropométricos y determinar si los trastornos que padecían se debían al deterioro nutricional directamente relacionado con el tiempo en diálisis. Materiales y Métodos: Es esta investigación realizó un seguimiento de 90 pacientes de ambos sexos con insuficiencia renal crónica, que recibían hemodiálisis periódicamente en la unidad renal de nuestro Hospital en Granada (España) durante un período de cinco años. La sangre de los pacientes se analizó trimestralmente para albúmina plasmática (Alb), colesterol total (TC) y proteínas totales (TP), y mensualmente para transferrina (Tr). Se tomaron medidas antropométricas de peso, talla e índice de masa corporal (IMC) de los pacientes y se les efectuaron mediciones antropométricas de peso, altura e índice de masa corporal calculado mediante la formula peso/talla², y agrupada según la clasificación de la OMS en IMC < 18.50 infrapeso, 18.50 a 24,99 normal, 25 a 29,99 sobrepeso y >30 del IMC s/OMS y se consideró para el estudio como desnutrición un en IMC < 23 kg/m2 y niveles de albumina <3,8 g/dl según el consenso del panel de expertos de la International Society for Renal Nutrition and Metabolism. Resultados: Durante los cinco años de nuestro estudio, los pacientes experimentaron una disminución estadísticamente significativa de proteínas totales (0,941 g/dl), albúmina plasmática (0,9382 g/dl), colesterol total (23,77 mg/dl) y transferrina (78,17. g /dl) p < 0,0001. Por el contrario, los valores medios del IMC no mostraron diferencias estadísticamente relevantes (p < 0,805). Sin embargo, todos los pacientes permanecieron en la categoría de sobrepeso de la OMS. Los valores de volumen corporal tampoco mostraron diferencias estadísticamente significativas. Conclusiones: La desnutrición de los pacientes en diálisis es un hecho patente, el IMC no se corresponde con los parámetros bioquímicos observados, por lo que el deterioro nutricional de estos pacientes se manifiesta principalmente mediante los parámetros bioquímicos estudiados.

Screw-retained internal connection zirconia CAD-CAM abutments in single implant reconstructions: Results of a 1-year prospective case series study.

PURPOSE: To evaluate the clinical and radiographic outcomes of single-tooth implant restorations using one-piece, internally connected, screw-retained, computer-aided design and computer-aided manufactured monolithic zirconia restorations fabricated on regular diameter implants. MATERIAL AND METHODS: Following a 2-stage surgical procedure, 22 implants placed in anterior and posterior areas in 21 partially edentulous patients (mean age of 55 years; 9 males/12 females) were evaluated in terms of plaque index, pocket probing depth, bleeding on probing, level of oral hygiene (OH), signs of mucositis/peri-implantitis, esthetic score (ES), gingival zenith position (GZP), papilla index score, the thickness of peri-implant gingiva, radiographic marginal bone loss, and technical complications. Implants and restorations were prospectively followed from the insertion of the restoration (baseline), up to 12-months post-loading. RESULTS: A 100% implant survival rate resulted after loading; one implant was lost before loading. Clinically, patients performed an adequate OH, and tissues were kept healthy. Probing depth showed a slightly lower value at baseline compared to any follow-up examination (2.26 [0.94] at baseline vs. 2.53 [0.66] mm at 12 months). ES, GZP, and the thickness of the peri-implant gingiva improved throughout the course of the study. Radiographically, average marginal bone level (MBL) was 0.40 (0.40) mm after 1-year follow-up with no differences in average MBL at all time points. Technically, after 1 year of clinical function, neither abutment fracture nor any other serious complications occurred. Hence, prosthetic reconstruction survival rate was 100%. CONCLUSIONS: Clinical outcomes of single-tooth implant restorations using internally connected, screw-retained, computer-aided design and computer-aided manufacturing monolithic zirconia abutments can be considered a reliable treatment alternative after 1-year clinical observation.

Computational Methods in Cooperation with Experimental Approaches to Design Protein Tyrosine Phosphatase 1B Inhibitors in Type 2 Diabetes Drug Design: A Review of the Achievements of This Century.

Protein tyrosine phosphatase 1B (PTP1B) dephosphorylates phosphotyrosine residues and is an important regulator of several signaling pathways, such as insulin, leptin, and the ErbB signaling network, among others. Therefore, this enzyme is considered an attractive target to design new drugs against type 2 diabetes, obesity, and cancer. To date, a wide variety of PTP1B inhibitors that have been developed by experimental and computational approaches. In this review, we summarize the achievements with respect to PTP1B inhibitors discovered by applying computer-assisted drug design methodologies (virtual screening, molecular docking, pharmacophore modeling, and quantitative structure-activity relationships (QSAR)) as the principal strategy, in cooperation with experimental approaches, covering articles published from the beginning of the century until the time this review was submitted, with a focus on studies conducted with the aim of discovering new drugs against type 2 diabetes. This review encourages the use of computational techniques and includes helpful information that increases the knowledge generated to date about PTP1B inhibition, with a positive impact on the route toward obtaining a new drug against type 2 diabetes with PTP1B as a molecular target.

Structure-Activity Relationship of N-Phenylthieno[2,3-b]pyridine-2-carboxamide Derivatives Designed as Forkhead Box M1 Inhibitors: The Effect of Electron-Withdrawing and Donating Substituents on the Phenyl Ring.

We report synthesis, characterization, biological evaluation, and molecular-docking studies of 18 thieno[2,3-b]pyridines with a phenylacetamide moiety at position 2, which is disubstituted with F, Cl, Br, or I at position 4, and with electron-withdrawing and electron-donating groups (-CN, -NO2, -CF3, and -CH3) at position 2, to study how the electronic properties of the substituents affected the FOXM1-inhibitory activity. Among compounds 1-18, only those bearing a -CN (regardless of the halogen) decreased FOXM1 expression in a triple-negative breast cancer cell line (MDA-MB-231), as shown by Western blotting. However, only compounds 6 and 16 decreased the relative expression of FOXM1 to a level lower than 50%, and hence, we determined their anti-proliferative activity (IC50) in MDA-MB-231 cells using the MTT assay, which was comparable to that observed with FDI-6, in contrast to compound 1, which was inactive according to both Western blot and MTT assays. We employed molecular docking to calculate the binding interactions of compounds 1-18 in the FOXM1 DNA-binding site. The results suggest a key role for residues Val296 and Leu289 in this binding. Furthermore, we used molecular electrostatic potential maps showing the effects of different substituents on the overall electron density.

Superparamagnetic Iron Oxide Nanoparticles Decorated Mesoporous Silica Nanosystem for Combined Antibiofilm Therapy.

A crucial challenge to face in the treatment of biofilm-associated infection is the ability of bacteria to develop resistance to traditional antimicrobial therapies based on the administration of antibiotics alone. This study aims to apply magnetic hyperthermia together with controlled antibiotic delivery from a unique magnetic-responsive nanocarrier for a combination therapy against biofilm. The design of the nanosystem is based on antibiotic-loaded mesoporous silica nanoparticles (MSNs) externally functionalized with a thermo-responsive polymer capping layer, and decorated in the outermost surface with superparamagnetic iron oxide nanoparticles (SPIONs). The SPIONs are able to generate heat upon application of an alternating magnetic field (AMF), reaching the temperature needed to induce a change in the polymer conformation from linear to globular, therefore triggering pore uncapping and the antibiotic cargo release. The microbiological assays indicated that exposure of E. coli biofilms to 200 µg/mL of the nanosystem and the application of an AMF (202 kHz, 30 mT) decreased the number of viable bacteria by 4 log10 units compared with the control. The results of the present study show that combined hyperthermia and antibiotic treatment is a promising approach for the effective management of biofilm-associated infections.

Immunogenicity profile in African green monkeys of a vaccine candidate based on a mutated form of human Interleukin-15.

BACKGROUND: Interleukin (IL)-15 is a proinflammatory T-cell growth factor overexpressed in several autoimmune diseases such as rheumatoid arthritis. Our initial strategy to neutralize the increased levels of IL-15 consisted in a vaccine candidate based on the recombinant modified human IL-15 (mhIL-15) mixed with the alum adjuvant. A previous study in non-human primates Macaca fascicularis has shown that vaccination induces neutralizing antibodies against native IL-15, without affecting animal behavior, clinical status, or the percentage of IL-15-dependent cell populations. However, the mhIL-15 used as an antigen was active in the IL-2-dependent cytotoxic T-cell line CTLL-2, which could hinder its therapeutic application. The current article evaluated the immunogenicity in African green monkeys of a vaccine candidate based on IL-15 mutant D8SQ108S, an inactive form of human IL-15. RESULTS: IL-15 D8SQ108S was inactive in the CTLL-2 bioassay but was able to competitively inhibit the biological activity of human IL-15. Immunization with 200 µg of IL-15 mutant combined with alum elicited anti-IL-15 IgG antibodies after the second and third immunizations. The median values of anti-IL-15 antibody titers were slightly higher than those generated in animals immunized with 200 µg of mhIL-15. The highest antibody titers were induced after the third immunization in monkeys vaccinated with 350 µg of IL-15 D8SQ108S. In addition, sera from immunized animals inhibited the biological activity of human IL-15 in CTLL-2 cells. The maximum neutralizing effect was observed after the third immunization in sera of monkeys vaccinated with the highest dose of the IL-15 mutant. These sera also inhibited the proliferative activity of simian IL-15 in the CTLL-2 bioassay and did not affect the IL-2-induced proliferation of the aforementioned T-cell line. Finally, it was observed that vaccination neither affects the animal behavior nor the general clinical parameters of immunized monkeys. CONCLUSION: Immunization with inactive IL-15 D8SQ108S mixed with alum generated neutralizing antibodies specific for human IL-15 in African green monkeys. Based on this fact, the current vaccine candidate could be more effective than the one based on biologically active mhIL-15 for treating autoimmune disorders involving an uncontrolled overproduction of IL-15.

May Measurement Month 2019: an analysis of blood pressure screening results in the Philippines.

The Philippine Society of Hypertension (PSH) took part again in the annual May Measurement Month 2019 (MMM19) blood pressure (BP) measurement campaign to raise awareness of hypertension especially in those who are not aware of their condition. The MMM19 standard protocol designed by the International Society of Hypertension was used during screening. These included the collection of basic data on demography, lifestyle, and environmental factors. Standardized sitting BP measurements were taken two to three times, using an automated BP apparatus and were inputted either in the MMM19 app or data were recorded in paper form and manually transferred to Excel spreadsheets by encoders supervised by the PSH. A total of 89 941 participated through opportunistic convenience sampling. After multiple imputation, a total of 47 925 (53.3%) participants had hypertension (≥140/90 mmHg or on antihypertensive medication). Of this number, 31 151 (65%) were aware that they had high BP and 30 120 (62.8%) were on antihypertensive medications. Of the 30 120 participants on antihypertensive medications, only 18 373 (61.1%) had controlled BP (<140/90 mmHg). Being overweight or obese were significant predictors of high BP. Other predictors of high systolic BP and diastolic BP were alcohol intake, smoking, and a previous history of hypertension in pregnancy, while pregnant participants had significantly lower BP. The MMM19 campaign succeeded in raising awareness of high BP in our country, and the opportunistic sampling enhanced a sense of people empowerment by their knowing how easy it is to detect high BP and thereby enabling the prevention of long-term health complications. The higher BP control in the MMM19 hypertensive individuals possibly attests to the success of the previous MMM17 and MMM18 campaigns.

Recent advances in neoadjuvant therapy for breast cancer.

Neoadjuvant trials for early breast cancer have accelerated the identification of novel active agents, enabling streamlined conduct of registration trials with fewer subjects. Measurement of neoadjuvant drug effects has also enabled the identification of patients with high risk of distant recurrence and has justified development of additional adjuvant approaches to improve outcomes. Neoadjuvant evaluation of new drugs was significantly improved by the introduction of pathologic complete response (pCR) rate as a quantitative surrogate endpoint for distant disease-free survival (DDFS) and event free survival (EFS). The neoadjuvant phase 2 platform trial I-SPY 2 simultaneously tests multiple drugs across multiple breast cancer subtypes using Bayesian methods of adaptive randomization for assessment of drug efficacy. In addition to the pCR endpoint, the I-SPY 2 trial has demonstrated that the residual cancer burden (RCB) score measures gradations of tumor response that correlate with DDFS and EFS across treatments and subtypes. For HER2-positive and triple-negative breast cancers that have failed to attain pCR with neoadjuvant chemotherapy (NAC), effective modifications of adjuvant treatment have improved outcomes and changed the standard of care for these subtypes. Neoadjuvant therapy is therefore preferred for stage II and III, as well as some stage I, HER2-positive and triple-negative tumors. Neoadjuvant endocrine therapy (NET) strategies have also emerged from innovative trials for stage II and III estrogen receptor (ER)-positive/HER2-negative tumors, as in the ALTERNATE trial. From neoadjuvant trials, opportunities have emerged to de-escalate therapy on the basis of metrics of response to chemotherapy or hormonal therapy. Neoadjuvant therapy for early breast cancer is therefore emerging as a promising approach to accelerate new drug development, optimize treatment strategies, and (where appropriate) de-escalate neoadjuvant therapy.

Emerging Strategies in Anticancer Combination Therapy Employing Silica-Based Nanosystems.

Combination therapy has emerged as one of the most promising approaches for cancer treatment. However, beyond remotely-triggered therapies that require advanced infrastructures and optimization, new combination therapies based on internally triggered cell-killing effects have also demonstrated promising therapeutic profiles. In this revision, the focus is on self-triggered strategies able to improve the therapeutic effect of drug delivery nanosystems. As reviewed, ferroptosis, hypoxia, and immunotherapy show potency enough to treat satisfactorily tumors in vivo. However, the interest of combining those with chemotherapeutics, especially with carriers based on mesoporous silica, has provided a new generation of therapeutic nanomedicines with potential enough to achieve complete tumor remission in murine models.

Chronic non-cancer pain management by nurses in specialist pain clinics.

BACKGROUND: Chronic non-cancer pain (CNCP) is one of the major causes of disability globally, and patients who suffer from it are a complex population, which makes it difficult to provide effective care. Specialist pain clinics and nursing professionals in them are the main care providers, but there is little research conducted in this field. AIM: To explore the attitudes and knowledge of nurses working in specialist pain clinics regarding care of CNCP patients. METHODS: Qualitative phenomenological approach. Sixteen semi-structured interviews were conducted in 2017 with nurses who worked in specialist pain clinics in six hospitals in southern Spain. RESULTS: Data analysis led to the formation of two categories, 'being trained and improving knowledge in CNCP' and 'the challenge of caring for patients with CNCP', and five subcategories. CONCLUSION: The need for care in CNCP is not covered by nurses in all the areas it requires. Lack of time, staffing issues, and specific training in this area makes it difficult to provide care. However, some areas for improvement are proposed, such as psychological interventions, group workshops, continuous training, and multidisciplinary teams.

The Association of Febuxostat Compared With Allopurinol on Blood Pressure and Major Adverse Cardiac Events Among Adult Patients With Hyperuricemia: A Meta-analysis.

Increased uric acid levels have been known to be associated with different cardiovascular and renal diseases. Over the past few years, several studies have examined the role of urate-lowering therapy (ULT) in hypertension and major adverse cardiac events (MACE) and suggest a potential role of elevated serum uric acid as an independent cardiovascular risk factor. This meta-analysis was done to determine the association of 2 ULTs commonly used in clinical practice (febuxostat vs. allopurinol) on hypertension and MACE and resolve the conflicting results of the outcomes of earlier studies. Randomized controlled trials comparing febuxostat versus allopurinol published with outcomes on blood pressure, all-cause mortality, myocardial infarction (MI), and stroke were searched through PubMed, Google Scholar, and Cochrane database. A total of 10 studies were subsequently included in the meta-analysis. Pooled analysis of the mean differences (MD) were done for the outcomes on blood pressure (systolic and diastolic) and risk ratios (RRs) for the outcomes on MACE with corresponding 95% confidence intervals (CIs). Pooled analysis of studies on hyperuricemic patients showed that febuxostat 40 mg has no significant difference compared with allopurinol 100/300 mg with respect to diastolic (MD, -0.56 with 95% CI of -4.28 to 3.15) and systolic blood pressure (MD, 0.30 with 95% CI of -3.33 to 3.93). No significant differences were also noted on all-cause mortality (RR, 1.18 with 95% CI of 0.99-1.41), MI (RR, 0.92 with 95% CI of 0.72-1.18), and stroke (RR, 1.05 with 95% CI of 0.77-1.43). The results of this meta-analysis showed that the 2 ULTs (febuxostat vs. allopurinol) have no significant association with respect to blood pressure among adult patients with hyperuricemia. No significant association was also noted of either ULT with all-cause mortality, MI, and stroke.

Mesoporous Silica Nanoparticles as Carriers for Therapeutic Biomolecules.

The enormous versatility of mesoporous silica nanoparticles permits the creation of a large number of nanotherapeutic systems for the treatment of cancer and many other pathologies. In addition to the controlled release of small drugs, these materials allow a broad number of molecules of a very different nature and sizes. In this review, we focus on biogenic species with therapeutic abilities (proteins, peptides, nucleic acids, and glycans), as well as how nanotechnology, in particular silica-based materials, can help in establishing new and more efficient routes for their administration. Indeed, since the applicability of those combinations of mesoporous silica with bio(macro)molecules goes beyond cancer treatment, we address a classification based on the type of therapeutic action. Likewise, as illustrative content, we highlight the most typical issues and problems found in the preparation of those hybrid nanotherapeutic materials.

A systematic review and meta-analysis on the effectiveness of an invasive strategy compared to a conservative approach in patients > 65 years old with non-ST elevation acute coronary syndrome.

BACKGROUND: Patients 65 years old and older largely represent (>50%) hospital-admitted patients with acute coronary syndrome (ACS). Data are conflicting comparing efficacy of early routine invasive (within 48-72 hours of initial evaluation) versus conservative management of ACS in this population. OBJECTIVE: We aimed to determine the effectiveness of routine early invasive strategy compared to conservative treatment in reducing major adverse cardiovascular events in patients 65 years old and older with non-ST elevation (NSTE) ACS. DATA SOURCES: We conducted a systematic review of randomized controlled trials (RCTs) through PubMed, Cochrane, and Google Scholar database. STUDY SELECTION: The studies included were RCTs that evaluated the effectiveness of invasive strategy compared to conservative treatment among patients ≥ 65 years old diagnosed with NSTEACS. Studies were included if they assessed any of the following outcomes of death, cardiovascular mortality, myocardial infarction (MI), stroke, recurrent angina, and need for revascularization. Six articles were subsequently included in the meta-analysis. DATA EXTRACTION: Three independent reviewers extracted the data of interest from the articles using a standardized data collection form that included study quality indicators. Disparity in assessment was adjudicated by another reviewer. DATA SYNTHESIS: All pooled analyses were initially done using Fixed Effects model. For pooled analyses with significant heterogeneity (I2≥ 50%), the Random Effects model was used. A total of 3,768 patients were included, 1,986 in the invasive strategy group, and 1,782 in the conservative treatment group. RESULTS: Meta-analysis showed less incidence of revascularization in the invasive (2%) over conservative treatment groups (8%), with overall risk ratio of 0.29 (95% CI 0.14 to 0.59). Across all pooled studies, no significant effect of invasive strategy on all-cause mortality, cardiovascular mortality, stroke, and MI was observed. Only one study assessed the outcome of recurrent angina. CONCLUSION: There was a significantly lower rate of revascularization in the invasive strategy group compared to the conservative treatment group. In the reduction of all-cause mortality, cardiovascular mortality, MI, and stroke there was no significant effect of invasive strategy versus conservative treatment. This finding does not support the bias against early routine invasive intervention in patients ≥ 65 years old with NSTEACS. Further studies focusing on these patients with larger population sizes are still needed.

Characterisation of the in vitro activity of a Nitazoxanide-N-methyl-1H-benzimidazole hybrid molecule against albendazole and nitazoxanide susceptible and resistant strains of Giardia intestinalis and its in vivo giardicidal activity.

BACKGROUND: It was previously demonstrated that CMC-20, a nitazoxanide and N-methyl-1H-benzimidazole hybrid molecule, had higher in vitro activity against Giardia intestinalis WB strain than metronidazole and albendazole and similar to nitazoxanide. OBJETIVES: To evaluate the in vitro activity of CMC-20 against G. intestinalis strains with different susceptibility/resistance to albendazole and nitazoxanide and evaluate its effect on the distribution of parasite cytoskeletal proteins and its in vivo giardicidal activity. METHODS: CMC-20 activity was tested against two isolates from patients with chronic and acute giardiasis, an experimentally induced albendazole resistant strain and a nitazoxanide resistant clinical isolate. CMC-20 effect on the distribution of parasite cytoskeletal proteins was analysed by indirect immunofluorescence and its activity was evaluated in a murine model of giardiasis. FINDINGS CMC-20: showed broad activity against susceptible and resistant strains to albendazole and nitaxozanide. It affected the parasite microtubule reservoir and triggered the parasite encystation. In this process, alpha-7.2 giardin co-localised with CWP-1 protein. CMC-20 reduced the infection time and cyst load in feces of G. muris infected mice similar to albendazole. MAIN CONCLUSIONS: The in vitro and in vivo giardicidal activity of CMC-20 suggests its potential use in the treatment of giardiasis.

Partial inhibition of the tricarboxylic acid cycle in Taenia crassiceps cysticerci after the in vitro exposure to a benzimidazole derivative (RCB15).

The benzimidazole derivative, 6-chloro-5-(2,3-dichlorophenoxy)-2-(trifluoromethyl)-1H-benzimidazole (RCB15), has a similar mode of action and efficacy as albendazole, a commonly used anthelminthic drugs. The aim of this study was to evaluate its influence on the tricarboxylic acid cycle in Taenia crassiceps cysticerci. The parasites were cultured in supplemented RPMI medium containing albendazole sulfoxide (ABZSO) or RCB15, for 24 h. Then, frozen in liquid nitrogen for organic metabolites extraction. Samples were analyzed by high performance liquid chromatography and organic acids of the tricarboxylic acid cycle were detected. It was possible to observe changes in the concentrations of all acids involved in this metabolic pathway, with the exception of α-ketoglutarate, which was not detected in the control group neither in most of the treated groups. It indicates that the parasite presented a partial inhibition of the tricarboxylic acid cycle. The significant increase in the concentration of citrate, oxaloacetate and succinate in the RCB15 treated groups may indicate an activation of the fumarate reductase pathway, leading to metabolic distress. Therefore RCB15 may be considered an alternative for the treatment of tissue parasitic diseases, since it induced changes in the main metabolic pathway of the parasite.

Characterisation of the in vitro activity of a Nitazoxanide-N-methyl-1H-benzimidazole hybrid molecule against albendazole and nitazoxanide susceptible and resistant strains of Giardia intestinalis and its in vivo giardicidal activity

BACKGROUND It was previously demonstrated that CMC-20, a nitazoxanide and N-methyl-1H-benzimidazole hybrid molecule, had higher in vitro activity against Giardia intestinalis WB strain than metronidazole and albendazole and similar to nitazoxanide. OBJETIVES To evaluate the in vitro activity of CMC-20 against G. intestinalis strains with different susceptibility/resistance to albendazole and nitazoxanide and evaluate its effect on the distribution of parasite cytoskeletal proteins and its in vivo giardicidal activity. METHODS CMC-20 activity was tested against two isolates from patients with chronic and acute giardiasis, an experimentally induced albendazole resistant strain and a nitazoxanide resistant clinical isolate. CMC-20 effect on the distribution of parasite cytoskeletal proteins was analysed by indirect immunofluorescence and its activity was evaluated in a murine model of giardiasis. FINDINGS CMC-20 showed broad activity against susceptible and resistant strains to albendazole and nitaxozanide. It affected the parasite microtubule reservoir and triggered the parasite encystation. In this process, alpha-7.2 giardin co-localised with CWP-1 protein. CMC-20 reduced the infection time and cyst load in feces of G. muris infected mice similar to albendazole. MAIN CONCLUSIONS The in vitro and in vivo giardicidal activity of CMC-20 suggests its potential use in the treatment of giardiasis.