Efficient Strategy to Synthesize Tunable pH-Responsive Hybrid Micelles Based on Iron Oxide and Gold Nanoparticles.

The preparation of multifunctional nanomaterials based on inorganic nanoparticles with organic materials has emerged as a promising strategy for the development of new nanomedicines for in vitro and in vivo biomedical applications. Here, we synthesized pH-responsive hybrid inorganic micelles by combining a novel pH-responsive amphiphilic molecule with hydrophobic payloads. This amphiphile was synthesized in a one-pot reaction and self-assembled readily into micelles under acidic pH conditions. In the presence of hydrophobic NP payloads such as AuNPs or IONPs, the amphiphile self-organized around them through hydrophobic interactions, resulting in the formation of colloidally stable hybrid micelles. The size of the hydrophobic NPs determined the pH-response of the inorganic hybrid micelles, which is tuned from pH 7 to 11 for our pH-responsive amphiphilic molecule. This achievement represents a novel approach for the synthesis of tunable pH-responsive hybrid micelles based on inorganic NPs for biomedical imaging, hyperthermia treatment, and also drug delivery nanosystems.

Sinonasal Adenocarcinoma: Clinicopathological Characterization and Prognostic Factors.

Sinonasal (SN) malignancies are rare. Within SN adenocarcinomas, the most frequent are intestinal-type adenocarcinomas (ITACs). ITAC has been associated with wood and leather dust occupational exposure and TP53 mutations. Not much information is available regarding its characterization and treatment. The aim of this study is to characterize the clinicopathologic and prognostic factors of patients with sinonasal adenocarcinomas (SNACs) treated in our tertiary-level hospital. A retrospective, consecutive study including SNAC patients diagnosed between 2004-2023 was conducted. Clinicopathological data was collected, and p53 status was assessed in the tumor specimens. The association between p53 status and clinicopathological variables, as well as their impact on survival, was evaluated. In total, 35 were included, most of them having ITAC (91.4%) with papillary subtype (37.5%); the majority were subjected to occupational risk exposure (82.9%). Overexpression of p53 was identified in 48.6% of the tumors. Papillary and colonic subtypes were associated with higher median progression-free survival (mPFS) than mucinous and solid subtypes (mPFS 37 months, 95% CI, 20.0-54.0, vs. 9 months, 95% CI, 7.15-10.85, p=0.01); the former was also associated with higher median overall survival (mOS) (mOS 64 months, 95% CI, 37.18-90.81 vs. 14 months, 95% CI, 0-41.58, p=0.02). Histologic grade 1-2 and macroscopic complete resection were associated with higher PFS (PFS of five months of 90.9% vs. 33.3%, p=0.01; mPFS of 37 months, 95% CI, 4.93-69.07 vs. 10 months, 95% CI, 6.43-13.57, p=0.04, respectively). Disease recurrence with distant metastases was associated with lower OS (11 months, 95% CI, 6.1-15.9 vs. 53 months, 95% CI, 22.70-83.30, p=0.04). This study reinforces the importance of protective occupational measures. Future studies will be important to validate the best treatment strategy in the advanced stages of this disease and also to identify new prognostic and/or therapeutic target biomarkers in SNAC.

Biological evaluation of carbohydrate-based aprepitant analogs for neuroblastoma treatment.

Different studies using Aprepitant, a NK1R antagonist currently used as a clinical drug for treating chemotherapy-related nausea and vomiting, have demonstrated that pharmacological inhibition of NK1R effectively reduces the growth of several tumor types such as neuroblastoma (NB). In a previous work, we demonstrated that a series of carbohydrate-based Aprepitant analogs, derived from either d-galactose or l-arabinose, have shown high affinity and NK1R antagonistic activity with a broad-spectrum anticancer activity and an important selectivity. In this new study, we explore the selective cytotoxic effects of these derivatives for the treatment of NB. Furthermore, we describe the design and stereoselective synthesis of a new generation of d-glucose derivatives as Aprepitant analogs, supported by docking studies. This approach showed that most of our carbohydrate-based analogs are significantly more selective than Aprepitant. The galactosyl derivative 2α, has demonstrated a marked in vitro selective cytotoxic activity against NB, with IC50 values in the same range as those of Aprepitant and its prodrug Fosaprepitant. Interestingly, the derivative 2α has shown similar apoptotic effect to that of Aprepitant. Moreover, we can select the glucosyl amino derivative 10α as an interesting hit exhibiting higher in vitro cytotoxic activity against NB than Aprepitant, being 1.2 times more selective.

Optimization of iron oxide nanoparticles for MRI-guided magnetic hyperthermia tumor therapy: reassessing the role of shape in their magnetocaloric effect.

Superparamagnetic iron oxide nanoparticles have hogged the limelight in different fields of nanotechnology. Surprisingly, notwithstanding the prominent role played as agents in magnetic hyperthermia treatments, the effects of nanoparticle size and shape on the magnetic hyperthermia performance have not been entirely elucidated yet. Here, spherical or cubical magnetic nanoparticles synthesized by a thermal decomposition method with the same magnetic and hyperthermia properties are evaluated. Interestingly, spherical nanoparticles displayed significantly higher magnetic relaxivity than cubic nanoparticles; however, comparable differences were not observed in specific absorption rate (SAR), pointing out the need for additional research to better understand the connection between these two parameters. Additionally, the as-synthetized spherical nanoparticles showed negligible cytotoxicity and, therefore, were tested in vivo in tumor-bearing mice. Following intratumoral administration of these spherical nanoparticles and a single exposure to alternating magnetic fields (AMF) closely mimicking clinical conditions, a significant delay in tumor growth was observed. Although further in vivo experiments are warranted to optimize the magnetic hyperthermia conditions, our findings support the great potential of these nanoparticles as magnetic hyperthermia mediators for tumor therapy.

Real-world experience of intravenous iron sucrose supplementation and dynamics of soluble transferrin receptor and hepcidin in a Spanish cohort of absolute iron deficient patients.

The study evaluated the safety and effectiveness of the generic intravenous (IV) iron treatment (Feriv®), in a Spanish cohort with absolute iron deficiency (ID) (serum ferritin <50 ng/ml, with or without anaemia) (n = 122; 91% women; median age of 44 years [IQR: 33.7-54]). Iron-related biomarkers were measured before treatment (baseline), 2 weeks after beginning the protocol (intermediate control, IC) and between 7 and 10 days after treatment completion (final time-point). Primary efficacy endpoints were ferritin levels ≥ 50 ng/ml, anaemia restoration or an increase in haemoglobin (Hb) of at least one point in patients without baseline anaemia. After treatment, iron-related biomarkers improved, including ferritin, Hb, sideremia, transferrin, transferrin saturation index, soluble transferrin receptor (sTfR), and hepcidin. Baseline ferritin concentration (13.5 ng/ml [IQR: 8-24.2]) increased at the IC and continued rising at the final time-point, reaching a median ferritin of 222 ng/ml and 97.3% of patients ≥ 50 ng/ml. At the final time-point, anaemia prevalence decreased from 26.2% to 5%, while the 34.1% without baseline anaemia showed an increase in Hb of at least one point. Headache was the only drug-adverse event recorded in 2.3% of patients. At a late time-point (27.5 median weeks after ending therapy [IQR: 22-40]), evaluated in a subgroup of 66 patients, 18% had ferritin levels < 50 ng/ml. Multivariate analysis showed that low baseline ferritin and high sTfR/hepcidin ratio tended to be independently associated with ID recurrence. Feriv® is a safe, effective first-line treatment for absolute ID, with improvement of serum ferritin and Hb. ID recurrence was associated with the baseline degree of iron stores depletion, indicated by serum ferritin, and sTfR/hepcidin ratio.

Dysregulation of iron metabolism modulators in virologically suppressed HIV-infected patients.

Background: Iron metabolism plays an essential role in cellular functions. Since virologically suppressed chronic HIV-infected subjects under effective antiretroviral treatment (ART) exhibit a persistent immune dysfunction that leads to comorbidities, iron homeostasis may be relevant in this context. We aimed to explore iron metabolism in virologically suppressed chronic HIV infected subjects under a successful ART. Methods: In this retrospective study, traditional iron metabolism biomarkers (total iron, ferritin, transferrin, and transferrin saturation index), as well as soluble transferrin receptor (sTfR), hepcidin, and inflammatory markers were determined in virologically suppressed chronic HIV-infected subjects under at least 2 years of ART (HIV) who also had >350 CD4-T-cells/mm3 (N=92) from Spain. As controls, we collected non-HIV age-matched healthy donors (Young, N=25) and elderly subjects (>65 years old; Elderly; N=25). Additionally, an external group of non-HIV patients with ferritin<50 ng/mL diagnosed with absolute iron deficiency (Ferropenic group; N=84) was included. Comparisons between groups were performed using Kruskal-Wallis or Mann-Whitney U-tests, while associations between variables were explored by Spearman's rho correlation coefficient. Results: We selected samples from HIV-infected subjects (aged 42[34-47], 95% males), young age-matched (aged 40[30-58], 60% males), and elderly controls (aged 82[78-88], 100% males). Compared to both healthy (Young and Elderly) groups, HIV exhibited decreased iron, transferrin saturation, and sTfR, and increased ferritin, but similar hepcidin levels. Notably, associations between sTfR and iron (Young, r=-0.587, p=0.002; Elderly, r=-0.496, p=0.012) or transferrin saturation index (Young, r=-0.581, p=0.002; Elderly, r=-0.489, p=0.013) were negative in both controls while positive in HIV (r=0.464, p<0.0001 and r=0.421, p<0.0001, respectively). Moreover, the expected negative correlation between hepcidin and sTfR, observed in controls (Young, r=-0.533, p=0.006; Elderly, r=-0.473, p=0.017), was absent in HIV (r=0.082; p=0.438). Interestingly, the HIV inflammatory profile differed from the Elderly one, who despite their inflammaging-related profile, succeed in maintaining these associations. Furthermore, subjects from the ferropenic group (aged 42[32-51], 5% males), showing significantly lower levels of hepcidin and higher sTfR, as expected, reflected similar correlations as those Young and Elderly, in contrast to HIV. Conclusions: Virologically suppressed chronic HIV-infected patients under successful ART exhibit altered levels of iron metabolism modulators suggesting a complex functional iron deficiency.

Threshold Ferritin Concentrations Reflecting Early Iron Deficiency Based on Hepcidin and Soluble Transferrin Receptor Serum Levels in Patients with Absolute Iron Deficiency.

(1) Background: The serum ferritin cut-off to define absolute iron deficiency is not well-established. The aim of the present study was to determine a clinically relevant ferritin threshold by using early serum biomarkers of iron deficiency such as hepcidin and the soluble transferrin receptor; (2) Methods: Two hundred and twenty-eight asymptomatic subjects attending a hospital as outpatients between 1st April 2020 and 27th February 2022 were selected. Iron metabolism parameters as part of the blood analysis were requested by their doctor and included in the study. Then, they were classified into groups according to their ferritin levels and iron-related biomarkers in serum were determined, quantified, and compared between ferritin score groups and anemic subjects. (3) Results: Serum ferritin levels below 50 ng/mL establish the point from which the serum biomarker, the soluble transferrin receptor to hepcidin ratio (sTfR/Hep ratio), begins to correlate significantly with ferritin levels. (4) Conclusion: Ferritin levels ≤ 50 ng/mL are indicative of early iron deficiency; hence, this should be considered as a clinically relevant cut-off for iron deficiency.

Prognostic Role of the Initial Grade of Dysplasia on Premalignant Vocal Fold Lesions.

PURPOSE: The main objective of this study was to analyze the prognostic role of the initial grade of dysplasia on the progression to SCC. STUDY DESIGN: Retrospective cohort. METHODS: This study was performed in the Otorhinolaryngology Department of a tertiary hospital center from January 2010 to December 2020. Every patient submitted to a microlaryngoscopy during this period with a histology of dysplasia on the first biopsy was included. RESULTS: A total of 112 patients were included and median follow-up was 24 months (range 1-120 months). Mean age at diagnosis was 59.71 (+/- 12.03) and 88 patients were male (78.6%). Initial grade of dysplasia was mild on 60 patients (53.6%), moderate on 24 (21.4%), severe on 18 (16.1%), and carcinoma in situ in 10 (8.9%). Overall, 25 patients (21.4%) developed invasive squamous cell carcinoma (SCC) and 15 (13.4%) died during follow-up. On an adjusted 5 year's progression free survival analysis, considering gender, age, dysplasia grade, tobacco and alcohol consumption, the initial grade of dysplasia was the only factor significantly associated with progression to carcinoma (P = .047). When compared to mild dysplasia, moderate dysplasia had a Hazard Ratio (HR) of 0.81 (95%CI 0.21-3.22); severe dysplasia had a HR of 1.76 (95%CI 0.59-5.30) and carcinoma in situ had a HR of 4.25 (95%CI 1.44-12.59). CONCLUSION: The initial dysplasia grade seems to be the most important prognostic factor regarding progression to SCC in patients with premalignant vocal fold disease.

Correction: Clickable iron oxide NPs based on catechol derived ligands: synthesis and characterization.

Correction for 'Clickable iron oxide NPs based on catechol derived ligands: synthesis and characterization' by Esther Pozo-Torres et al., Soft Matter, 2020, 16, 3257-3266, DOI: 10.1039/C9SM02512J.

Passive targeting of high-grade gliomas via the EPR effect: a closed path for metallic nanoparticles?

Passive tumor targeting via the enhanced permeability and retention (EPR) effect has long been considered the most effective mechanism for the accumulation of nanoparticles inside solid tumors. However, several studies have demonstrated that the EPR effect is largely dependent on the tumor type and location. Particularly complex is the situation in brain tumors, where the presence of the blood-brain tumor barrier (BBTB) adds an extra limiting factor in reaching the tumor interstitium. However, it remains unclear whether these restraints imposed by the BBTB prevent the EPR effect from acting as an efficient tumor targeting mechanism for metallic nanoparticles. In this work, we have studied the EPR effect of metallic magnetic nanoparticles (MMNPs) in a glioblastoma (GBM) model by parametric MRI. Our results showed that only MMNPs ≤50 nm could reach the tumor interstitium, whereas larger MMNPs were unable to cross the BBTB. Furthermore, even for MMNPs around 30-50 nm, the amount of them found within the tumor was scarce and restricted to the vicinity of large tumor vessels, indicating that the BBTB strongly limits the passive accumulation of metallic nanoparticles in brain tumors. Therefore, active targeting becomes the most reasonable strategy to target metallic nanoparticles to GBMs.

Carbohydrate-Based NK1R Antagonists with Broad-Spectrum Anticancer Activity.

NK1R antagonists, investigated for the treatment of several pathologies, have shown encouraging results in the treatment of several cancers. In the present study, we report on the synthesis of carbohydrate-based NK1R antagonists and their evaluation as anticancer agents against a wide range of cancer cells. All of the prepared compounds, derived from either d-galactose or l-arabinose, have shown high affinity and NK1R antagonistic activity with a broad-spectrum anticancer activity and an important selectivity, comparable to Cisplatin. This strategy has allowed us to identify the galactosyl derivative 14α, as an interesting hit exhibiting significant NK1R antagonist effect (kinact 0.209 ± 0.103 µM) and high binding affinity for NK1R (IC50 = 50.4 nM, Ki = 22.4 nM by measuring the displacement of [125I] SP from NK1R). Interestingly, this galactosyl derivative has shown marked selective cytotoxic activity against 12 different types of cancer cell lines.

Fe3O4-Au Core-Shell Nanoparticles as a Multimodal Platform for In Vivo Imaging and Focused Photothermal Therapy.

In this study, we report the synthesis of gold-coated iron oxide nanoparticles capped with polyvinylpyrrolidone (Fe@Au NPs). The as-synthesized nanoparticles (NPs) exhibited good stability in aqueous media and excellent features as contrast agents (CA) for both magnetic resonance imaging (MRI) and X-ray computed tomography (CT). Additionally, due to the presence of the local surface plasmon resonances of gold, the NPs showed exploitable "light-to-heat" conversion ability in the near-infrared (NIR) region, a key attribute for effective photothermal therapies (PTT). In vitro experiments revealed biocompatibility as well as excellent efficiency in killing glioblastoma cells via PTT. The in vivo nontoxicity of the NPs was demonstrated using zebrafish embryos as an intermediate step between cells and rodent models. To warrant that an effective therapeutic dose was achieved inside the tumor, both intratumoral and intravenous routes were screened in rodent models by MRI and CT. The pharmacokinetics and biodistribution confirmed the multimodal imaging CA capabilities of the Fe@AuNPs and revealed constraints of the intravenous route for tumor targeting, dictating intratumoral administration for therapeutic applications. Finally, Fe@Au NPs were successfully used for an in vivo proof of concept of imaging-guided focused PTT against glioblastoma multiforme in a mouse model.

Inter- and intraspecific variation in juvenile metabolism and water loss among five biphasic amphibian species.

Population persistence is informed by the ability of individuals to cope with local abiotic conditions, which is commonly mediated by physiological traits. Among biphasic amphibians, juveniles-which are infrequently studied but play a key role in amphibian population dynamics-are the first life stage to experience terrestrial conditions following the aquatic larval stage. To illuminate phenotypic variation that may allow juveniles to survive the physiological challenges presented by this transition, we examined respiratory surface area water loss (RSAWL) and standard metabolic rates (SMR) among juveniles reared under common larval conditions for five salamander species (Ambystoma annulatum, A. maculatum, A. opacum, A. talpoideum, and A. texanum) collected across ~ 200 km of latitude in Missouri, USA. We found that SMR described 34% of variation in RSAWL, suggesting that physiological water conservation may be limited by energetic regulation among these species, and vice versa. On average, species differed in juvenile SMR and residual values of RSAWL (corrected for body size/shape) by 0.04 mL [Formula: see text] and 0.16, respectively, possibly because of distinct species ecologies. For example, A. annulatum had higher SMR and RSAWL compared to broadly distributed study species, potentially associated with a relatively narrow range of environmental conditions experienced across the small geographic distribution of A. annulatum. Latitude correlated negatively with temperature and precipitation, and positively with RSAWL, suggesting that variation in RSAWL may be adaptive to local conditions. We provide evidence that species differences likely have a genetic basis, reflecting selection favoring species divergence to effectively use distinct microhabitats.

Surgical outcomes of sinonasal inverted papilloma: a 17 year review / Resultados cirúrgicos do papiloma invertido nasossinusal: uma revisão de 17 anos

Abstract Introduction: Inverted papillomas represent one of the most common benign neoplasic lesions located in the sinonasal tract. Owing to the local erosive behavior, tendency to recur and the potential for malignant transformation, surgical management of inverted papillomas is often challenging. Objective: This study aimed to analyze the surgical outcomes of patients with inverted papillomas, according to the Krouse staging and the different surgical approaches. Methods: Retrospective study of patients diagnosed with sinonasal inverted papillomas who underwent surgical treatment between 2000 and 2016 at a tertiary referral hospital. Cases with follow-up less than 12 months were excluded. The rate and the time of recurrence were the main outcomes. Values of p < 0.05 were considered statistically significant. Results: Thirty-six cases with mean age of 60 years, predominantly male (72%), were included. The follow-up period ranged from 1 to 16 years, with an average of 4.5 years. Krouse T1 Stage corresponded to 11.1%; T2 occurred in 50% of cases; while T3 and T4 Stages accounted for 30.6% and 8.3% of patients, respectively. Most cases were approached by an endoscopic technique alone (83.3%), with a recurrence rate of 13.3%. Patients treated via a combined or open approach revealed a recurrence of 16.7%. No differences in the recurrence rate were reported when comparing endoscopic surgery with the open or combined techniques. Krouse Stage T3 had a significant association with inverted papillomas recurrence (p = 0.023). All inverted papilloma relapses occurred up to 2 years post-operatively. One case of malignant transformation was recorded (2.7%). Conclusion: Endoscopic surgery did not increase the recurrence rates and can be a safe and efficient alternative to open or combined techniques. The recurrence of inverted papillomas seem to be related to the persistence of the disease and tend to occur early after primary surgery. Krouse T3 Stages may be associated with a higher recurrence of inverted papillomas.

Resumo Introdução: Os papilomas invertidos são uma das lesões neoplásicas benignas mais comuns no trato nasossinusal. Devido ao seu comportamento localmente agressivo, tendência para recidivar e potencial de malignização, o tratamento cirúrgico dos papilomas invertidos constitui frequentemente um desafio. Objetivo: Analisar os resultados cirúrgicos dos papilomas invertidos segundo o estadiamento de Krouse, bem como avaliar as diferentes abordagens cirúrgicas. Método: Estudo retrospectivo de pacientes com diagnóstico de papiloma invertido nasossinusal submetidos a tratamento cirúrgico entre 2000 e 2016 em hospital terciário. Casos com acompanhamento inferior a 12 meses foram excluídos. A taxa e o tempo de recidiva foram os principais resultados analisados desfechos avaliados. Valores p < 0,05 foram considerados estatisticamente significativos. Resultados: Foram incluídos 36 casos, com média de idade de 60 anos, predominantemente do sexo masculino (72%). O período de acompanhamento variou de 1 a 16 anos, em uma média de 4,5 anos. Relativamente ao estadiamento, 11,1% dos pacientes foram classificados como estadio Krouse T1, 50% como T2, 30,6% como T3 e 8,3% como T4. A maioria dos casos foi tratada exclusivamente por cirurgia endoscópica (83,3%), com taxa de recidiva de 13,3%. Pacientes tratados com uma técnica combinada ou aberta apresentaram recidiva de 16,7%. Não foram observadas diferenças quanto à taxa de recidiva entre os casos abordados por via endoscópica e os casos tratados com técnica aberta ou combinada. Verificou-se uma associação significativa entre o estadio T3 de Krouse e recidiva de papilomas invertidos (p = 0,023). Todas as recidivas de papilomas invertidos foram observadas até dois anos após a cirurgia. Um caso de transformação maligna foi registrado (2,7%). Conclusão: A cirurgia endoscópica não aumentou as taxas de recidiva e pode ser uma alternativa segura e eficiente às técnicas abertas ou combinadas. Os casos de recidiva do papiloma invertido parecem estar relacionados com a persistência da doença e tendem a ocorrer precocemente após a cirurgia primária. Os estadios T3 de Krouse podem estar associados a uma maior recidiva.

Magnetic Nanoparticles as MRI Contrast Agents.

Iron oxide nanoparticles (IONPs) have emerged as a promising alternative to conventional contrast agents (CAs) for magnetic resonance imaging (MRI). They have been extensively investigated as CAs due to their high biocompatibility and excellent magnetic properties. Furthermore, the ease of functionalization of their surfaces with different types of ligands (antibodies, peptides, sugars, etc.) opens up the possibility of carrying out molecular MRI. Thus, IONPs functionalized with epithelial growth factor receptor antibodies, short peptides, like RGD, or aptamers, among others, have been proposed for the diagnosis of various types of cancer, including breast, stomach, colon, kidney, liver or brain cancer. In addition to cancer diagnosis, different types of IONPs have been developed for other applications, such as the detection of brain inflammation or the early diagnosis of thrombosis. This review addresses key aspects in the development of IONPs for MRI applications, namely, synthesis of the inorganic core, functionalization processes to make IONPs biocompatible and also to target them to specific tissues or cells, and finally in vivo studies in animal models, with special emphasis on tumor models.

Risk, Diagnostic and Predictor Factors for Classical Hodgkin Lymphoma in HIV-1-Infected Individuals: Role of Plasma Exosome-Derived miR-20a and miR-21.

The incidence of classical Hodgkin lymphoma (cHL) in the HIV-1 setting has increased 5-25-fold compared to that observed in the general population. This study aimed to determine whether selected micro RNAs (miRs) and other soluble biomarkers and cellular subsets are dysregulated in cHL and could be used as biomarkers. This was a retrospective and longitudinal matched case-control study of 111 Caucasian, HIV-1-infected adult individuals, including 37 individuals with cHL and 74 with no type of cancer. Immunovirological data, plasma exosome-derived miR-16, miR-20a, miR-21, miR-221, miR-223, miR-106a, miR-185, miR-23, miR-30d, miR-222, miR-146a and miR-324, plasma IL-6, sCD14, sCD27, sCD30, sIL-2R, TNFR1, and cell phenotyping of T and B lymphocytes and natural killer (NK) cells were analyzed. Before cHL diagnosis, miR-20a, miR-21, and sCD30 were higher in cHL (p = 0.008, p = 0.009 and p = 0.042, respectively), while miR-16 was down-regulated (p = 0.040). miR-20a and miR-21 were independently associated with cHL (p = 0.049 and p = 0.035, respectively). The combination of miR-20a and miR-21 showed a good AUC value of 0.832 with a moderate likelihood ratio positive (LR+) value of 5.6 and a slight likelihood ratio negative (LR-) value of 0.23. At cHL diagnosis, miR-20a, miR-21 and miR-324 were overexpressed in cHL (p = 0.005, p = 0.024, and p = 0.001, respectively), while miR-223, miR-16, miR-185 and miR-106a were down regulated (p = 0.042, p = 0.007, p = 0.006, and p = 0.002, respectively). In addition, sCD14, sCD27, sCD30 and IL2R levels were higher in these individuals (p = 0.038, p = 0.010, p = 0.030, p = 0.006, respectively). miR-20a was independently associated with cHL (p = 0.011). The diagnostic value of miR-20a showed good AUC value of 0.754 (p = 0.074) with a slight LR+ value of 2 and a slight LR- of 0.25. After chemotherapy, miR-20a was higher in those individuals who had an adverse outcome (p < 0.001), while sCD14 and sCD30 were higher (p < 0.001). A specific signature of miRs and cytokines associated with a subsequent cHL diagnosis was found in this study, especially miR-20a and miR-21. Also, another biomarker signature was found at cHL diagnosis, with a relevant discriminant disease value for miR-20a. Of note, miR-20a expression was higher in those individuals who had an adverse clinical outcome after chemotherapy.

Clickable iron oxide NPs based on catechol derived ligands: synthesis and characterization.

Clickable magnetic nanoparticles have attracted great attention as potential nanoplatforms for biomedical applications because of the high functionalization efficiency of their surfaces with biomolecules, which facilitates their bio-compatibilization. However, the design and synthesis of clickable NPs is still challenging because of the complexity of the chemistry on the magnetic NP surface, thus robust methods that improve the ligand synthesis and the transfer of magnetic NPs in physiological media being in high-demand. In this work, we developed a versatile and enhanced synthetic route to fabricate potentially clickable IONPs of interest in nanomedicine. Catechol anchor ligands with different stereo-electronic features were synthetized from a hetero bi-functional PEG spacer backbone. The resulting catechol ligands transferred in good yields and high stability to magnetic NPs by an improved energetic ligand exchange method that combines sonication and high temperature. The azido functionalized IONPs exhibited excellent characteristics as T2 MRI contrast agents with low cytotoxicity, making these clickable magnetic NPs promising precursors for nanomedicines.

New signatures of poor CD4 cell recovery after suppressive antiretroviral therapy in HIV-1-infected individuals: involvement of miR-192, IL-6, sCD14 and miR-144.

Up to 40% of newly diagnosed cases of HIV-1 infection are late diagnoses, with a profound decrease in CD4 cell counts in many cases. One-third of these individuals do not achieve optimal CD4 cell recovery (OR) after suppressive antiretroviral treatment (ART). This retrospective/longitudinal study of poor recovery (PR) included 79 HIV-1-infected individuals with CD4 count <200 cells/mm3 (25 PR and 54 OR) before ART. After suppressive ART, 21 PR and 24 OR individuals were further analysed, including paired samples. Selected miRs and plasma inflammatory markers were determined to investigate their potential predictive/diagnostic value for poor recovery. miR-192, IL-6 and sCD14 were independently associated with CD4 recovery before ART (p = 0.031, p = 0.007, and p = 0.008, respectively). The combination of these three factors returned a good discrimination (predictive value for PR) value of 0.841 (AUC, p < 0.001). After suppressive ART, miR-144 was independently associated with CD4 recovery (p = 0.017), showing a moderate discrimination value of 0.730 (AUC, p = 0.008) for PR. Our study provides new evidence on the relationship between miRs and HIV-1 infection that could help improve the management of individuals at HIV-1 diagnosis. These miRs and cytokines signature sets provide novel tools to predict CD4 cell recovery and its progression after ART.

Surgical outcomes of sinonasal inverted papilloma: a 17 year review.

INTRODUCTION: Inverted papillomas represent one of the most common benign neoplasic lesions located in the sinonasal tract. Owing to the local erosive behavior, tendency to recur and the potential for malignant transformation, surgical management of inverted papillomas is often challenging. OBJECTIVE: This study aimed to analyze the surgical outcomes of patients with inverted papillomas, according to the Krouse staging and the different surgical approaches. METHODS: Retrospective study of patients diagnosed with sinonasal inverted papillomas who underwent surgical treatment between 2000 and 2016 at a tertiary referral hospital. Cases with follow-up less than 12 months were excluded. The rate and the time of recurrence were the main outcomes. Values of p<0.05 were considered statistically significant. RESULTS: Thirty-six cases with mean age of 60 years, predominantly male (72%), were included. The follow-up period ranged from 1 to 16 years, with an average of 4.5 years. Krouse T1 Stage corresponded to 11.1%; T2 occurred in 50% of cases; while T3 and T4 Stages accounted for 30.6% and 8.3% of patients, respectively. Most cases were approached by an endoscopic technique alone (83.3%), with a recurrence rate of 13.3%. Patients treated via a combined or open approach revealed a recurrence of 16.7%. No differences in the recurrence rate were reported when comparing endoscopic surgery with the open or combined techniques. Krouse Stage T3 had a significant association with inverted papillomas recurrence (p=0.023). All inverted papilloma relapses occurred up to 2 years post-operatively. One case of malignant transformation was recorded (2.7%). CONCLUSION: Endoscopic surgery did not increase the recurrence rates and can be a safe and efficient alternative to open or combined techniques. The recurrence of inverted papillomas seem to be related to the persistence of the disease and tend to occur early after primary surgery. Krouse T3 Stages may be associated with a higher recurrence of inverted papillomas.

Combination of G2-S16 dendrimer/dapivirine antiretroviral as a new HIV-1 microbicide.

Aim: To research the synergistic activity of G2-S16 dendrimer and dapivirine (DPV) antiretroviral as microbicide candidate to prevent HIV-1 infection. Materials & methods: We assess the toxicity of DPV on cell lines by MTT assay, the anti-HIV-1 activity of G2-S16 and DPV alone or combined at several fixed ratios. Finally, their ability to inhibit the bacterial growth in vitro was assayed. The analysis of combinatorial effects and the effective concentrations were performed with CalcuSyn software. Conclusion: Our results represent the first proof-of-concept study of G2-S16/DPV combination to develop a safe microbicide.