Solid Lipid Nanoparticles: Multitasking Nano-Carriers for Cancer Treatment.

Despite all the advances seen in recent years, the severe adverse effects and low specificity of conventional chemotherapy are still challenging problems regarding cancer treatment. Nanotechnology has helped to address these questions, making important contributions in the oncological field. The use of nanoparticles has allowed the improvement of the therapeutic index of several conventional drugs and facilitates the tumoral accumulation and intracellular delivery of complex biomolecules, such as genetic material. Among the wide range of nanotechnology-based drug delivery systems (nanoDDS), solid lipid nanoparticles (SLNs) have emerged as promising systems for delivering different types of cargo. Their solid lipid core, at room and body temperature, provides SLNs with higher stability than other formulations. Moreover, SLNs offer other important features, namely the possibility to perform active targeting, sustained and controlled release, and multifunctional therapy. Furthermore, with the possibility to use biocompatible and physiologic materials and easy scale-up and low-cost production methods, SLNs meet the principal requirements of an ideal nanoDDS. The present work aims to summarize the main aspects related to SLNs, including composition, production methods, and administration routes, as well as to show the most recent studies about the use of SLNs for cancer treatment.

Novel UGT1A1 Gene Mutations in a Boy with Crigler-Najjar Syndrome Type II.

In this article, we reported a patient with Crigler-Najjar syndrome type II with high-unconjugated bilirubin levels that decreased after phenobarbital treatment. The patient had two novel missense mutations in the UGT1A1 gene and a promoter variant in one allele. One mutation was c.1001T > C, that predicted leucine to proline substitution at position 334 (p.Leu334Pro). The other, c.1139A > G, predicted glutamic acid to glycine replacement at position 380 (p.Glu380Gly). In silico analysis indicated that both mutations are likely pathogenic.

Risk Factors for COVID-19 Morbidity and Mortality in Institutionalised Elderly People.

BACKGROUND: SARS-CoV-2 has caused a high mortality in institutionalised individuals. There are very few studies on the involvement and the real impact of COVID-19 in nursing homes. This study analysed factors related to morbidity and mortality of COVID-19 in institutionalised elderly people. METHODS: This cohort study included 842 individuals from 12 nursing homes in Sant Cugat del Vallès (Spain) from 15 March to 15 May 2020. We evaluated individual factors (demographic, dependence, clinical, and therapeutic) and those related to the nursing homes (size and staff) associated with infection and mortality by SARS-CoV-2. Infection was diagnosed by molecular biology test. RESULTS: Of the 842 residents included in the analysis, 784 underwent a Polymerase Chain Reaction (PCR) test; 74.2% were women, the mean age was 87.1 years, and 11.1% died. The PCR test was positive in 44%. A total of 33.4% of the residents presented symptoms compatible with COVID-19 and of these, 80.9% were PCR-positive for SARS-CoV-2. Infection by SARS-CoV-2 among residents was associated with the rate of staff infected in the homes. Mortality by SARS-CoV-2 was related to male sex and a greater grade of dependence measured with the Barthel index. CONCLUSIONS: SARS-Cov-2 infection in institutionalised people is associated with the infection rate in nursing home workers and mortality by SARS-Cov-2 with sex and greater dependency according to the Barthel index. Adequate management of nursing home staff and special attention to measures of infection control, especially of individuals with greater dependence, are keys for successful management of future pandemic situations.

Thermo-responsive hydrogels for cancer local therapy: Challenges and state-of-art.

Despite the enormous efforts done by the scientific community in the last decades, advanced cancer is still considered an incurable disease. New formulations are continuously under investigation to improve drugs therapeutic index, i.e., increase chemotherapeutic efficacy and reduce adverse effects. In this context, hydrogels-based systems for drug local sustained/controlled release have been proposed to reduce off-target effects caused by the repeated administration of systemic/oral anticancer drugs and improve their therapeutic effectiveness. Moreover, it increases the patient welfare by reducing the number of administrations needed. Among the several types of existing hydrogels, the thermo-responsive ones, which are able to change their physical state from liquid at 25 °C to a gel at the body temperature, i.e., 37 °C, gained special attention as in situ sustained drug release depot-systems in cancer treatment. To date, several thermo-responsive hydrogels have been used for drugs and/or genetic material delivery, yielding promising results both at preclinical and clinical evaluation stages. This culminates in the market authorization of Jelmyto® for the treatment of urothelial cancer. Here are summarized and discussed the last 10 years advances regarding the application of thermo-responsive hydrogels in local cancer treatment.

Polymeric micelles targeted against CD44v6 receptor increase niclosamide efficacy against colorectal cancer stem cells and reduce circulating tumor cells in vivo.

Colorectal cancer (CRC) is a highly prevalent disease worldwide. Patient survival is hampered by tumor relapse and the appearance of drug-resistant metastases, which are sustained by the presence of cancer stem cells (CSC). Specific delivery of anti-CSC chemotherapeutic drugs to tumors by using targeted drug delivery systems that can also target CSC sub-population might substantially improve current clinical outcomes. CD44v6 is a robust biomarker for advanced CRC and CSC, due to its functional role in tumorigenesis and cancer initiation process. Here, we show that CD44v6-targeted polymeric micelles (PM) loaded with niclosamide (NCS), a drug against CSC, is a good therapeutic strategy against colorectal CSC and circulating tumor cells (CTC) in vivo. HCT116 cells were sorted according to their CD44v6 receptor expression into CD44v6+ (high) and CDv44v6- (low) subpopulations. Accordingly, CD44v6+ cells presented stemness properties, such as overexpression of defined stemness markers (ALDH1A1, CD44v3 and CXCR4) and high capacity to form colonspheres in low attachment conditions. NCS-loaded PM functionalized with an antibody fragment against CD44v6 (Fab-CD44v6) presented adequate size, charge, and encapsulation efficiency. In addition, Fab-CD44v6 significantly increased PM internalization in CD44v6+ cells. Further, encapsulation of NCS improved its effectiveness in vitro, particularly against colonspheres, and allowed to increase its intravenous dosage in vivo by increasing the amount of NCS able to be administered without causing toxicity. Remarkably, functionalized PM accumulate in tumors and significantly reduce CTC in vivo. In conclusion, CD44v6 targeted PM meet the essential conditions to become an efficient anti-CSC therapy.

Correction to: Auditory and frontal anatomic correlates of pitch discrimination in musicians, non­musicians, and children without musical training.

In the original version of the article, the abstract section was missed to be added, and the abstract should read as below.

Auditory and frontal anatomic correlates of pitch discrimination in musicians, non-musicians, and children without musical training.

Individual differences in pitch discrimination have been associated with the volume of both the bilateral Heschl's gyrus and the right inferior frontal gyrus (IFG). However, most of these studies used samples composed of individuals with different amounts of musical training. Here, we investigated the relationship between pitch discrimination and individual differences in the gray matter (GM) volume of these brain structures in 32 adult musicians, 28 adult non-musicians, and 32 children without musical training. The results showed that (i) the individuals without musical training (whether children or adults) who were better at pitch discrimination had greater volume of auditory regions, whereas (ii) musicians with better pitch discrimination had greater volume of the IFG. These results suggest that the relationship between pitch discrimination and the volume of auditory regions is innately established early in life, and that musical training modulates the volume of the IFG, probably improving audio-motor connectivity. This is the first study to detect a relationship between pitch discrimination ability and GM volume before beginning any musical training in children and adults.

Active bilingualism delays the onset of mild cognitive impairment.

Lifelong bilingualism may contribute to cognitive reserve (CR) in neurodegenerative diseases as shown by a delay of the age at symptom onset in bilinguals with Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI). However, some studies have failed to show this bilingual advantage, suggesting that it might depend on the type and degree of bilingualism. In the present study, we tested the hypothesis that active bilingualism, defined as the continuous use of the two languages as opposed to second language exposition only, may protect against cognitive decline. Moreover, we investigated whether bilingualism as a CR factor may be explained by an advantage within the executive control (EC) system. To do so, we collected clinical measures (age at onset of cognitive symptoms, age at the first medical visit for cognitive impairments, and age at diagnosis) in patients with MCI and patients with AD with different degrees of language experience and usage of Catalan and Spanish. Additionally, all participants were tested on four EC tasks and one long-term memory recognition task. First, results from multiple regression analyses showed that active bilingualism was a significant predictor of delay in the age at onset for all the clinical measures in MCI, but not AD patients. Second, the effect of active bilingualism was independent of occupation, educational level and job attainment across the individuals' lifespan. Finally, although we did not find an effect of active bilingualism across all EC tasks, we did find an effect for conflict resolution. These results are discussed in the context of CR hypotheses, suggesting that compensatory mechanisms may play a role in protecting against cognitive decline.

Intracellular Delivery of Anti-SMC2 Antibodies against Cancer Stem Cells.

Structural maintenance of chromosomes protein 2 (SMC2) is a central component of the condensin complex involved in DNA supercoiling, an essential process for embryonic stem cell survival. SMC2 over-expression has been related with tumorigenesis and cancer malignancy and its inhibition is regarded as a potential therapeutic strategy even though no drugs are currently available. Here, we propose to inhibit SMC2 by intracellular delivery of specific antibodies against the SMC2 protein. This strategy aims to reduce cancer malignancy by targeting cancer stem cells (CSC), the tumoral subpopulation responsible of tumor recurrence and metastasis. In order to prevent degradation and improve cellular internalization, anti-SMC2 antibodies (Ab-SMC2) were delivered by polymeric micelles (PM) based on Pluronic® F127 amphiphilic polymers. Importantly, scaffolding the Ab-SMC2 onto nanoparticles allowed its cellular internalization and highly increased its efficacy in terms of cytotoxicity and inhibition of tumorsphere formation in MDA-MB-231 and HCT116 breast and colon cancer cell lines, respectively. Moreover, in the case of the HCT116 cell line G1, cell-cycle arrest was also observed. In contrast, no effects from free Ab-SMC2 were detected in any case. Further, combination therapy of anti-SMC2 micelles with paclitaxel (PTX) and 5-Fluorouracil (5-FU) was also explored. For this, PTX and 5-FU were respectively loaded into an anti-SMC2 decorated PM. The efficacy of both encapsulated drugs was higher than their free forms in both the HCT116 and MDA-MB-231 cell lines. Remarkably, micelles loaded with Ab-SMC2 and PTX showed the highest efficacy in terms of inhibition of tumorsphere formation in HCT116 cells. Accordingly, our data clearly suggest an effective intracellular release of antibodies targeting SMC2 in these cell models and, further, strong cytotoxicity against CSC, alone and in combined treatments with Standard-of-Care drugs.

Left-handed musicians show a higher probability of atypical cerebral dominance for language.

Music processing and right hemispheric language lateralization share a common network in the right auditory cortex and its frontal connections. Given that the development of hemispheric language dominance takes place over several years, this study tested whether musicianship could increase the probability of observing right language dominance in left-handers. Using a classic fMRI language paradigm, results showed that atypical lateralization was more predominant in musicians (40%) than in nonmusicians (5%). Comparison of left-handers with typical left and atypical right lateralization revealed that: (a) atypical cases presented a thicker right pars triangularis and more gyrified left Heschl's gyrus; and (b) the right pars triangularis of atypical cases showed a stronger intra-hemispheric functional connectivity with the right angular gyrus, but a weaker interhemispheric functional connectivity with part of the left Broca's area. Thus, musicianship is the first known factor related to a higher prevalence of atypical language dominance in healthy left-handed individuals. We suggest that differences in the frontal and temporal cortex might act as shared predisposing factors to both musicianship and atypical language lateralization.

A cross-sectional and longitudinal study on the protective effect of bilingualism against dementia using brain atrophy and cognitive measures.

BACKGROUND: Evidence from previous studies suggests that bilingualism contributes to cognitive reserve because bilinguals manifest the first symptoms of Alzheimer's disease (AD) up to 5 years later than monolinguals. Other cross-sectional studies demonstrate that bilinguals show greater amounts of brain atrophy and hypometabolism than monolinguals, despite sharing the same diagnosis and suffering from the same symptoms. However, these studies may be biased by possible pre-existing between-group differences. METHODS: In this study, we used global parenchymal measures of atrophy and cognitive tests to investigate the protective effect of bilingualism against dementia cross-sectionally and prospectively, using a sample of bilinguals and monolinguals in the same clinical stage and matched on sociodemographic variables. RESULTS: Our results suggest that the two groups did not differ in their cognitive status at baseline, but bilinguals had less parenchymal volume than monolinguals, especially in areas related to brain atrophy in dementia. In addition, a longitudinal prospective analysis revealed that monolinguals lost more parenchyma and had more cognitive decline than bilinguals in a mean follow-up period of 7 months. CONCLUSION: These results provide the first prospective evidence that bilingualism may act as a neuroprotective factor against dementia and could be considered a factor in cognitive reserve.

Separate Contribution of Striatum Volume and Pitch Discrimination to Individual Differences in Music Reward.

Individual differences in the level of pleasure induced by music have been associated with the response of the striatum and differences in functional connectivity between the striatum and the auditory cortex. In this study, we tested whether individual differences in music reward are related to the structure of the striatum and the ability to discriminate pitch. We acquired a 3-D magnetization-prepared rapid-acquisition gradient-echo image for 32 musicians and 26 nonmusicians who completed a music-reward questionnaire and a test of pitch discrimination. The analysis of both groups together showed that sensitivity to music reward correlated negatively with the volume of both the caudate and nucleus accumbens and correlated positively with pitch-discrimination abilities. Moreover, musicianship, pitch discrimination, and caudate volume significantly predicted individual differences in music reward. These results are consistent with the proposal that individual differences in music reward depend on the interplay between auditory abilities and the reward network.

Brain networks involved in accented speech processing.

We investigated the neural correlates of accented speech processing (ASP) with an fMRI study that overcame prior limitations in this line of research: we preserved intelligibility by using two regional accents that differ in prosody but only mildly in phonetics (Latin American and Castilian Spanish), and we used independent component analysis to identify brain networks as opposed to isolated regions. ASP engaged a speech perception network composed primarily of structures related with the processing of prosody (cerebellum, putamen, and thalamus). This network also included anterior fronto-temporal areas associated with lexical-semantic processing and a portion of the inferior frontal gyrus linked to executive control. ASP also recruited domain-general executive control networks related with cognitive demands (dorsal attentional and default mode networks) and the processing of salient events (salience network). Finally, the reward network showed a preference for the native accent, presumably revealing people's sense of social belonging.

Working Memory Deficits After Lesions Involving the Supplementary Motor Area.

The Supplementary Motor Area (SMA)-located in the superior and medial aspects of the superior frontal gyrus-is a preferential site of certain brain tumors and arteriovenous malformations, which often provoke the so-called SMA syndrome. The bulk of the literature studying this syndrome has focused on two of its most apparent symptoms: contralateral motor and speech deficits. Surprisingly, little attention has been given to working memory (WM) even though neuroimaging studies have implicated the SMA in this cognitive process. Given its relevance for higher-order functions, our main goal was to examine whether WM is compromised in SMA lesions. We also asked whether WM deficits might be reducible to processing speed (PS) difficulties. Given the connectivity of the SMA with prefrontal regions related to executive control (EC), as a secondary goal we examined whether SMA lesions also hampered EC. To this end, we tested 12 patients with lesions involving the left (i.e., the dominant) SMA. We also tested 12 healthy controls matched with patients for socio-demographic variables. To ensure that the results of this study can be easily transferred and implemented in clinical practice, we used widely-known clinical neuropsychological tests: WM and PS were measured with their respective Wechsler Adult Intelligence Scale indexes, and EC was tested with phonemic and semantic verbal fluency tasks. Non-parametric statistical methods revealed that patients showed deficits in the executive component of WM: they were able to sustain information temporarily but not to mentally manipulate this information. Such WM deficits were not subject to patients' marginal PS impairment. Patients also showed reduced phonemic fluency, which disappeared after controlling for the influence of WM. This observation suggests that SMA damage does not seem to affect cognitive processes engaged by verbal fluency other than WM. In conclusion, WM impairment needs to be considered as part of the SMA syndrome. These findings represent the first evidence about the cognitive consequences (other than language) of damage to the SMA. Further research is needed to establish a more specific profile of WM impairment in SMA patients and determine the consequences of SMA damage for other cognitive functions.

Predication drives verb cortical signatures.

Verbs and nouns are fundamental units of language, but their neural instantiation remains poorly understood. Neuropsychological research has shown that nouns and verbs can be damaged independently of each other, and neuroimaging research has found that several brain regions respond differentially to the two word classes. However, the semantic-lexical properties of verbs and nouns that drive these effects remain unknown. Here we show that the most likely candidate is predication: a core lexical feature involved in binding constituent arguments (boy, candies) into a unified syntactic-semantic structure expressing a proposition (the boy likes the candies). We used functional neuroimaging to test whether the intrinsic "predication-building" function of verbs is what drives the verb-noun distinction in the brain. We first identified verb-preferring regions with a localizer experiment including verbs and nouns. Then, we examined whether these regions are sensitive to transitivity--an index measuring its tendency to select for a direct object. Transitivity is a verb-specific property lying at the core of its predication function. Neural activity in the left posterior middle temporal and inferior frontal gyri correlates with transitivity, indicating sensitivity to predication. This represents the first evidence that grammatical class preference in the brain is driven by a word's function to build predication structures.

The missing link between faces and names: evidence from Alzheimer's disease patients.

Retrieval of proper names is a cause of concern and complaint among elderly adults and it is an early symptom of patients suffering from neurodegenerative diseases such as Alzheimer's disease (AD). While it is well established that AD patients have deficits of proper name retrieval, the nature of such impairment is not yet fully understood. Specifically, it is unknown whether this deficit is due to a degradation of the links between faces and proper names, or due to deficits in intentionally accessing and retrieving proper names from faces. Here, we aim to investigate the integrity of the links between famous faces and proper names in AD while minimizing the impact of the explicit retrieval. We compare the performances of AD patients and elderly controls in a face-name priming task. We assess the integrity of the link between faces and names at two different levels: identity level - the name and face belong to the same person; and semantic level - the name and face belong to the same category (e.g., politicians). Our results reveal that AD patients compared with controls show intact semantic priming but reduced priming for person identity. This suggests that the deficits in intentionally retrieving proper names in AD are the result of a partial disruption of the network at the identity level, i.e., the links between known faces and proper names.

On the parallel deterioration of lexico-semantic processes in the bilinguals' two languages: evidence from Alzheimer's disease.

In this article we aimed to assess how Alzheimer's disease (AD), which is neurodegenerative, affects the linguistic performance of early, high-proficient bilinguals in their two languages. To this end, we compared the Picture Naming and Word Translation performances of two groups of AD patients varying in disease progression (Mild and Moderate) with that of bilingual individuals diagnosed with mild cognitive impairment (MCI). The results revealed that the linguistic deterioration caused by AD affected the two languages similarly. We also found that cognate status and word frequency were two major determinants of language performance in all three groups of participants. These results are consistent with the notion of a common neural substrate recruited to represent and process the two languages of high-proficient bilinguals.

Bilingualism tunes the anterior cingulate cortex for conflict monitoring.

Monitoring and controlling 2 language systems is fundamental to language use in bilinguals. Here, we reveal in a combined functional (event-related functional magnetic resonance imaging) and structural neuroimaging (voxel-based morphometry) study that dorsal anterior cingulate cortex (ACC), a structure tightly bound to domain-general executive control functions, is a common locus for language control and resolving nonverbal conflict. We also show an experience-dependent effect in the same region: Bilinguals use this structure more efficiently than monolinguals to monitor nonlinguistic cognitive conflicts. They adapted better to conflicting situations showing less ACC activity while outperforming monolinguals. Importantly, for bilinguals, brain activity in the ACC, as well as behavioral measures, also correlated positively with local gray matter volume. These results suggest that early learning and lifelong practice of 2 languages exert a strong impact upon human neocortical development. The bilingual brain adapts better to resolve cognitive conflicts in domain-general cognitive tasks.

Escaping capture: bilingualism modulates distraction from working memory.

We ask whether bilingualism aids cognitive control over the inadvertent guidance of visual attention from working memory and from bottom-up cueing. We compare highly-proficient Catalan-Spanish bilinguals with Spanish monolinguals in three visual search conditions. In the working memory (WM) condition, attention was driven in a top-down fashion by irrelevant objects held in WM. In the Identify condition, attention was driven in a bottom-up fashion by visual priming. In the Singleton condition, attention was driven in a bottom-up fashion by including a unique distracting object in the search array. The results showed that bilinguals were overall faster than monolinguals in the three conditions, replicating previous findings that bilinguals can be more efficient than monolinguals in the deployment of attention. Interestingly, bilinguals were less captured by irrelevant information held in WM but were equally affected by visual priming and unique singletons in the search displays. These observations suggest that bilingualism aids top-down WM-mediated guidance of attention, facilitating processes that keep separate representations in WM from representations that guide visual attention. In contrast, bottom-up attentional capture by salient yet unrelated input operates similarly in bilinguals and monolinguals.