Carbon Nanohorns as Effective Nanotherapeutics in Cancer Therapy

Different carbon nanostructures have been explored as functional materials for the development of effective nanomaterials in cancer treatment applications. This review mainly aims to discuss the features, either strength or weakness, of carbon nanohorn (CNH), carbon conical horn-shaped nanostructures of sp2 carbon atoms. The interest for these materials arises from their ability to couple the clinically relevant properties of carbon nanomaterials as drug carriers with the negligible toxicity described in vivo. Here, we offer a comprehensive overview of the recent advances in the use of CNH in cancer treatments, underlining the benefits of each functionalization route and approach, as well as the biological performances of either loaded and unloaded materials, while discussing the importance of delivery devices

Leukocyte Integrin Antagonists as a Novel Option to Treat Dry Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is a complex multifactorial degenerative disease that leads to irreversible blindness. AMD affects the macula, the central part of the retina responsible for sharp central vision. Retinal pigment epithelium (RPE) is the main cellular type affected in dry AMD. RPE cells form a monolayer between the choroid and the neuroretina and are in close functional relationship with photoreceptors; moreover, RPE cells are part of the blood retina barrier that is disrupted in ocular diseases such as AMD. During ocular inflammation lymphocytes and macrophages are recruited, contact RPE and produce pro-inflammatory cytokines, which play an important role in AMD pathogenesis. The interaction between RPE and immune cells is mediated by leukocyte integrins, heterodimeric transmembrane receptors, and adhesion molecules, including VCAM-1 and ICAM-1. Within this frame, this study aimed to characterize RPE-leukocytes interaction and to investigate any potentially beneficial effects induced by integrin antagonists (DS-70, MN27 and SR714), developed in previous studies. ARPE-19 cells were co-cultured for different incubation times with Jurkat cells and apoptosis and necrosis levels were analyzed by flow cytometry. Moreover, we measured the mRNA levels of the pro-inflammatory cytokine IL-1\u3b2 and the expression of adhesion molecules VCAM-1 and ICAM-1. We found that RPE-lymphocyte interaction increased apoptosis and necrosis levels in RPE cells and the expression of IL-1\u3b2. This interaction was mediated by the binding of \u3b14\u3b21 and \u3b1L\u3b22 integrins to VCAM-1 and ICAM-1, respectively. The blockade of RPE-lymphocyte interaction with blocking antibodies highlighted the pivotal role played by integrins. Therefore, \u3b14\u3b21 and \u3b1L\u3b22 integrin antagonists were employed to disrupt RPE-lymphocyte crosstalk. Small molecule integrin antagonists proved to be effective in reducing RPE cell death and expression of IL-1\u3b2, demonstrating that integrin antagonists could protect RPE cells from detrimental effects induced by the interaction with immune cells recruited to the retina. Overall, the leukocyte integrin antagonists employed in the present study may represent a novel opportunity to develop new drugs to fight dry AMD

Multiple Lines of Evidence for a Potentially Seismogenic Fault Along the Central-Apennine (Italy) Active Extensional Belt–An Unexpected Outcome of the MW6.5 Norcia 2016 Earthquake

The Apenninic chain, in central Italy, has been recently struck by the Norcia 2016 seismic sequence. Three mainshocks, in 2016, occurred on August 24 (MW6.0), October 26 (MW 5.9) and October 30 (MW6.5) along well-known late Quaternary active WSW-dipping normal faults. Coseismic fractures and hypocentral seismicity distribution are mostly associated with failure along the Mt Vettore-Mt Bove (VBF) fault. Nevertheless, following the October 26 shock, the aftershock spatial distribution suggests the activation of a source not previously mapped beyond the northern tip of the VBF system. In this area, a remarkable seismicity rate was observed also during 2017 and 2018, the most energetic event being the April 10, 2018 (MW4.6) normal fault earthquake. In this paper, we advance the hypothesis that the Norcia seismic sequence activated a previously unknown seismogenic source. We constrain its geometry and seismogenic behavior by exploiting: 1) morphometric analysis of high-resolution topographic data; 2) field geologic- and morphotectonic evidence within the context of long-term deformation constraints; 3) 3D seismological validation of fault activity, and 4) Coulomb stress transfer modeling. Our results support the existence of distributed and subtle deformation along normal fault segments related to an immature structure, the Pievebovigliana fault (PBF). The fault strikes in NNW-SSE direction, dips to SW and is in right-lateral en echelon setting with the VBF system. Its activation has been highlighted by most of the seismicity observed in the sector. The geometry and location are compatible with volumes of enhanced stress identified by Coulomb stress-transfer computations. Its reconstructed length (at least 13 km) is compatible with the occurrence of MW≥6.0 earthquakes in a sector heretofore characterized by low seismic activity. The evidence for PBF is a new observation associated with the Norcia 2016 seismic sequence and is consistent with the overall tectonic setting of the area. Its existence implies a northward extent of the intra-Apennine extensional domain and should be considered to address seismic hazard assessments in central Italy

Dynamic spectral signatures of mirror movements in the sensorimotor functional connectivity network of patients with Kallmann syndrome

In Kallmann syndrome (KS), the peculiar phenomenon of bimanual synkinesis or mirror movement (MM) has been associated with a spectral shift, from lower to higher frequencies, of the resting-state fMRI signal of the large-scale sensorimotor brain network (SMN). To possibly determine whether a similar frequency specificity exists across different functional connectivity SMN states, and to capture spontaneous transitions between them, we investigated the dynamic spectral changes of the SMN functional connectivity in KS patients with and without MM symptom. Brain MRI data were acquired at 3 Tesla in 39 KS patients (32 without MM, KSMM-, seven with MM, KSMM+) and 26 age- and sex-matched healthy control (HC) individuals. The imaging protocol included 20-min rs-fMRI scans enabling detailed spectro-temporal analyses of large-scale functional connectivity brain networks. Group independent component analysis was used to extract the SMN. A sliding window approach was used to extract the dynamic spectral power of the SMN functional connectivity within the canonical physiological frequency range of slow rs-fMRI signal fluctuations (0.01-0.25 Hz). K-means clustering was used to determine (and count) the most recurrent dynamic states of the SMN and detect the number of transitions between them. Two most recurrent states were identified, for which the spectral power peaked at a relatively lower (state 1) and higher (state 2) frequency. Compared to KS patients without MM and HC subjects, the SMN of KS patients with MM displayed significantly larger spectral power changes in the slow 3 canonical sub-band (0.073-0.198 Hz) and significantly fewer transitions between state 1 (less recurrent) and state 2 (more recurrent). These findings demonstrate that the presence of MM in KS patients is associated with reduced spontaneous transitions of the SMN between dynamic functional connectivity states and a higher recurrence and an increased spectral power change of the high-frequency state. These results provide novel information about the large-scale brain functional dynamics that could help to understand the pathologic mechanisms of bimanual synkinesis in KS syndrome and, potentially, other neurological disorders where MM may also occur

Role of endoscopic endonasal approach for craniopharyngiomas extending into the third ventricle in adults

Introduction. Recent advancements in endoscopic endonasal approach (EEA) have favored its adoption for craniopharyngiomas extended to 3rd ventricle (3VCPs). However, for lack of extensive series, its outcome, limits, and indications remain debated. Research question. To assess the EEA results of for 3VCPs and identify those factors determining the choice of this approach. Material and Methods. Records of patients with 3VCPs, consecutively operated through an EEA at our Institution were retrospectively analyzed. Demographic and clinico-radiological data, rate of tumor resection, complications and outcome at follow-up were collected. Results. Thirty-six patients (19 females, mean age: 51.1 ± 15.9 yrs) were included. Extended transplanum-transtuberculum approach was performed in all cases Radical resection was achieved in 33 patients (91.7%). At follow-up, visual deficits improved/normalized in 21 cases (58.3%), and 35 (97.2%) presented with panhypopituitarism and DI. Anatomical (displacement of the chiasm and hypothalamus), clinical (age and pre-operative visual and endocrinological function) and tumoral (consistency, presence of hydrocephalus) parameters resulted relevant in determining the choice of this approach. Discussion and Conclusion. EEA offers a valid and direct route for 3VCPs, which permits to safely manage these tumors. In our series, EEA was chosen for tubero-infundibular forms with chiasm displaces antero-superiorly, and preferred in younger patients, with visual disturbances, comprimesed endocrinological function and no hydrocephalus. It requires a specific training and should be reserved in dedicated centers. Because no single approach is ideal for every 3VCP, all surgical options should be considered as complementary and selected basing on clinical, anatomical and tumoral features of each case

Distinct disease phenotypes linked to different combinations of GAA mutations in a large late-onset GSDII sibship

Background: Glycogenosis type II (GSDII or Pompe disease) is an autosomal recessive disease, often characterized by a progressive accumulation of glycogen within lysosomes caused by a deficiency of \u3b1-1,4-glucosidase (GAA; acid maltase), a key enzyme of the glycogen degradation pathway. To date, more than 326 different mutations in the GAA gene have been identified in patients with GSDII but the course of the disease is difficult to be predicted on the basis of molecular genetic changes. Studies on large informative families are advisable to better define how genetics and non genetics factors like exercise and diet may influence the clinical phenotype. Methods and results. In this study, we report on clinical, instrumental, and pathological features as well as on molecular analysis of a family with 10 out of 13 siblings affected by late-onset Pompe disease. Three mutations segregated in the family, two of which are novel mutations. Siblings showing a more severe phenotype were compound heterozygous for c.118C > T [p.R40X] and c.2647-7G > A [p.N882fs] on GAA, whereas, two patients showing a mild phenotype were compound heterozygous c.2647-7G > A [p.N882fs] and c.2276G > C [p.G759A] mutations. Quantitative expression analysis showed, in the patients carrying p.R40X/ p.N882fs, a significant (p 0.01) correlation between the levels of expression of the mutated allele and the age at onset of the disease. Conclusions: As far as we know, this is the largest informative family with late-onset Pompe disease described in the literature showing a peculiar complex set of mutations of GAA gene that may partially elucidate the clinical heterogeneity of this family. \ua9 2013 Sampaolo et al.; licensee BioMed Central Ltd

589 External validation of the increased wall thickness score for the diagnosis of cardiac amyloidosis

Abstract Aims This study aimed to validate the increased wall thickness (IWT) score, a multiparametric echocardiographic score to facilitate diagnosis of cardiac amyloidosis (CA), in an independent population of patients with increased LV wall thickness suspicious for CA. Methods and results Between January 2019 and December 2020, 152 consecutive patients with increased LV wall thickness suspicious for CA were included. For all patient, the multiparametric echocardiographic score (IWT score) was calculated. To validate the diagnostic accuracy of an IWT score ≥8 to predict the diagnosis of CA, sensibility (Se), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV), and predictive accuracy (PA) were calculated. Among the 152 patients included in the study, 50 (33%) were diagnosed as CA, 25 (16%) had severe aortic stenosis, 25 (16%) had hypertensive remodelling, and 52 (34%) had hypertrophic cardiomyopathy. Among the 50 and 102 patients with and without CA, 19 (38%) and 1 (1%) showed an IWT score ≥8, respectively. Overall, the diagnostic accuracy of an IWT score ≥8 for the diagnosis of CA in our population was the following: Se 38% (95% CI: 25–53%); Sp 99% (95% CI: 95–100%); PPV 95% (95% CI: 72–99%); NPV 77% (95% CI: 73–80%); PA 79% (95% CI: 72–85%). Conclusions This study reports the first external validation of the IWT score for the diagnosis of CA in patients with increased LV wall thickness. A score ≥8 showed a high Sp, PPV and PA, suggesting that the IWT score can be used to identify CA patients in those with increased LV wall thickness