Zika Virus: A Neurotropic Warrior against High-Grade Gliomas-Unveiling Its Potential for Oncolytic Virotherapy.

Gliomas account for approximately 75-80% of all malignant primary tumors in the central nervous system (CNS), with glioblastoma multiforme (GBM) considered the deadliest. Despite aggressive treatment involving a combination of chemotherapy, radiotherapy, and surgical intervention, patients with GBM have limited survival rates of 2 to 5 years, accompanied by a significant decline in their quality of life. In recent years, novel management strategies have emerged, such as immunotherapy, which includes the development of vaccines or T cells with chimeric antigen receptors, and oncolytic virotherapy (OVT), wherein wild type (WT) or genetically modified viruses are utilized to selectively lyse tumor cells. In vitro and in vivo studies have shown that the Zika virus (ZIKV) can infect glioma cells and induce a robust oncolytic activity. Consequently, interest in exploring this virus as a potential oncolytic virus (OV) for high-grade gliomas has surged. Given that ZIKV actively circulates in Colombia, evaluating its neurotropic and oncolytic capabilities holds considerable national and international importance, as it may emerge as an alternative for treating highly complex gliomas. Therefore, this literature review outlines the generalities of GBM, the factors determining ZIKV's specific tropism for nervous tissue, and its oncolytic capacity. Additionally, we briefly present the progress in preclinical studies supporting the use of ZIKV as an OVT for gliomas.

Nano-Immunomodulation: A New Strategy for Skeletal Muscle Diseases and Aging?

The skeletal muscle has a very remarkable ability to regenerate upon injury under physiological conditions; however, this regenerative capacity is strongly diminished in physio-pathological conditions, such as those present in diseased or aged muscles. Many muscular dystrophies (MDs) are characterized by aberrant inflammation due to the deregulation of both the lymphoid and myeloid cell populations and the production of pro-inflammatory cytokines. Pathological inflammation is also observed in old muscles due to a systemic change in the immune system, known as "inflammaging". Immunomodulation represents, therefore, a promising therapeutic opportunity for different skeletal muscle conditions. However, the use of immunomodulatory drugs in the clinics presents several caveats, including their low stability in vivo, the need for high doses to obtain therapeutically relevant effects, and the presence of strong side effects. Within this context, the emerging field of nanomedicine provides the powerful tools needed to control the immune response. Nano-scale materials are currently being explored as biocarriers to release immunomodulatory agents in the damaged tissues, allowing therapeutic doses with limited off-target effects. In addition, the intrinsic immunomodulatory properties of some nanomaterials offer further opportunities for intervention that still need to be systematically explored. Here we exhaustively review the state-of-the-art regarding the use of nano-sized materials to modulate the aberrant immune response that characterizes some physio-pathological muscle conditions, such as MDs or sarcopenia (the age-dependent loss of muscle mass). Based on our learnings from cancer and immune tolerance induction, we also discuss further opportunities, challenges, and limitations of the emerging field of nano-immunomodulation.

Shaping modern human skull through epigenetic, transcriptional and post-transcriptional regulation of the RUNX2 master bone gene.

RUNX2 encodes the master bone transcription factor driving skeletal development in vertebrates, and playing a specific role in craniofacial and skull morphogenesis. The anatomically modern human (AMH) features sequence changes in the RUNX2 locus compared with archaic hominins' species. We aimed to understand how these changes may have contributed to human skull globularization occurred in recent evolution. We compared in silico AMH and archaic hominins' genomes, and used mesenchymal stromal cells isolated from skull sutures of craniosynostosis patients for in vitro functional assays. We detected 459 and 470 nucleotide changes in noncoding regions of the AMH RUNX2 locus, compared with the Neandertal and Denisovan genomes, respectively. Three nucleotide changes in the proximal promoter were predicted to alter the binding of the zinc finger protein Znf263 and long-distance interactions with other cis-regulatory regions. By surface plasmon resonance, we selected nucleotide substitutions in the 3'UTRs able to affect miRNA binding affinity. Specifically, miR-3150a-3p and miR-6785-5p expression inversely correlated with RUNX2 expression during in vitro osteogenic differentiation. The expression of two long non-coding RNAs, AL096865.1 and RUNX2-AS1, within the same locus, was modulated during in vitro osteogenic differentiation and correlated with the expression of specific RUNX2 isoforms. Our data suggest that RUNX2 may have undergone adaptive phenotypic evolution caused by epigenetic and post-transcriptional regulatory mechanisms, which may explain the delayed suture fusion leading to the present-day globular skull shape.

Cambios en la ergonomía en tiempos de COVID-19 en estudiantes de una universidad Peruana / Changes in ergonomics in times of COVID-19 in students of a Peruvian university

La enfermedad por COVID-19 ha traído consigo cambios que forman parte de la nueva normalidad. Muchos de estos cambios podrían repercutir de mala manera en la población y traer enfermedades o riesgo de comorbilidades como diabetes, estrés, obesidad o problemas ergonómicos. El presente estudio tuvo como objetivo evaluar los factores asociados a la ergonomía en estudiantes universitarios durante el contexto de clases virtuales en Lima, Perú debido a la COVID-19. Se realizó una encuesta virtual mediante la plataforma de Google Forms, a 121 estudiantes del primer ciclo en una universidad limeña. La encuesta contenía preguntas sobre los cambios ergonómicos percibidos durante las clases virtuales debido a la COVID-19. Respecto al peso, 43.85 % presentó variación, mientras que el 44,6% reportó que no. Sobre las molestias corporales y visuales el 83.5 % presentaron dolores musculares, mientras que el 16.5 % no tenían estas molestias. Entre estos prevalecían el dolor de espalda, cuello, cintura, hombros y piernas. Por otro lado, el 78.5 % presentaban incomodidad visual, mientras que el otro 21.5 % no lo presentó. Entre las molestias visuales más frecuentes estaban ardor, picazón, sensación de ojo seco, cansancio de la vista y lagrimeo durante las clases. El dispositivo más usado por los estudiantes para las clases virtuales fue la laptop (81 %). Respecto a los ejercicios físicos, el 46,3 % sí lo realizaban terminada las clases, y los estiramientos un 62.8 %. Igualmente, se evaluó la ingesta de líquidos, frutas y comida chatarra. De los encuestados, un 52.9 % no varió su ingesta de líquidos, el 60.3 % no varió el de frutas, y el 48.8 % disminuyó la ingesta de comida chatarra. Los problemas ergonómicos que se evaluaron, podrían estar relacionados con los altos periodos de tiempo que los estudiantes se exponen al uso de los equipos electrónicos debido a las clases virtuales y también al no tener un lugar fijo de estudio, por lo que se debería realizar otras actividades adicionales como hacer ejercicio y/o estiramientos después de clase, además de ingerir más frutas, líquidos y mantener un estilo de vida saludable.

The increasing attention that is given to the protection of health professionals and patients has stimulated researchers and organizations to create alternatives to improve safety practices in health services, including in the Magnetic Resonance Imaging (MRI) environment. However, this theme still needs to be further explored in the MRI field. This paper aims to review the current literature, explore the approach to the MRI Safety Supervisor, to describe the role of the MRI Safety Supervisor and how it could serve as an agent to enhance the safety of health professionals and patients in the MRI environment. To achieve this, a narrative literature review was carried out in the electronic databases: ScienceDirect, PubMed, Scielo and Google Scholar, using as inclusion criteria, articles published in Portuguese and English between the years 2008 to 2019. The articles were filtered according to relevant aspects, such as authorship, title, year of publication, objectives, methodology and main results. Lastly, it considered aspects related to adverse events, international and national regulations on security and safety management in the MRI sector. Nevertheless, in the search for actions that effectively mitigate risks on this modality, it was observed that studies on the MRI Safety Supervisor are scarce, which reinforce the need for further studies on this matter.

Abdominal Wall Reconstruction with a Free Fibula Flap after Internal Extended Hemipelvectomy.

Major pelvic resections for malignant tumors are infrequent and have significant morbidity and mortality, for instance, incisional hernias are postoperative complications uncommonly reported probably because most cases are overshadowed by more serious complications. Reconstruction depends on the extent of the resection and overall prognosis of the patient. A case of a late complex hypogastric and femoral incisional hernia after extended hemipelvectomy for recurrent osteosarcoma treated with distal abdominal wall fixation into a free fibula flap is reported.

Treatment of Neuroma of the Dorsal Branch of the Ulnar Nerve With Transfer to the Distal Anterior Interosseous Nerve.

Painful neuromas of the dorsal branch of the ulnar nerve may be difficult to treat. Proximal transposition is the standard treatment, but pain may recur. Sensory-to-motor nerve transfer as an evolution of targeted muscle reinnervation is a recently described technique to reduce neuroma formation in the treatment of painful neuromas. This report describes sensory-to-motor transfer of the dorsal branch of the ulnar nerve to the distal anterior interosseous nerve to treat a painful neuroma.

Levator Palpebrae Superioris Muscle Direct Neurotization.

Direct muscle neurotization has been proved to be a feasible technique for facial reanimation microsurgical procedures. Direct muscle neurotization is performed by implanting the interposition nerve graft directly into the substance of the muscle. The authors present the case of a 36-year-old male patient with upper eyelid dysfunction secondary to facial trauma. The levator palpebrae superioris muscle was macroscopically unaffected; however, neurophysiological test proved a selective denervation of the CN III motor branch to the levator palpebrae superioris muscle. Direct muscle neurotization was performed by means of 2 separate nerve procedures. The authors have made follow-up for 3 months after surgery. The authors have noted development of upper eyelid movement meaning adequate function of the neurotized muscle. The authors believe that this procedure could be integrated into the surgical options to treat selective nerve injuries should the right patient is encountered.

Pharmacological inhibition of EZH2 as a promising differentiation therapy in embryonal RMS.

BACKGROUND: Embryonal Rhabdomyosarcoma (RMS) is a pediatric soft-tissue sarcoma derived from myogenic precursors that is characterized by a good prognosis in patients with localized disease. Conversely, metastatic tumors often relapse, leading to a dismal outcome. The histone methyltransferase EZH2 epigenetically suppresses skeletal muscle differentiation by repressing the transcription of myogenic genes. Moreover, de-regulated EZH2 expression has been extensively implied in human cancers. We have previously shown that EZH2 is aberrantly over-expressed in RMS primary tumors and cell lines. Moreover, it has been recently reported that EZH2 silencing in RD cells, a recurrence-derived embryonal RMS cell line, favors myofiber-like structures formation in a pro-differentiation context. Here we evaluate whether similar effects can be obtained also in the presence of growth factor-supplemented medium (GM), that mimics a pro-proliferative microenvironment, and by pharmacological targeting of EZH2 in RD cells and in RD tumor xenografts. METHODS: Embryonal RMS RD cells were cultured in GM and silenced for EZH2 or treated with either the S-adenosylhomocysteine hydrolase inhibitor 3-deazaneplanocin A (DZNep) that induces EZH2 degradation, or with a new class of catalytic EZH2 inhibitors, MC1948 and MC1945, which block the catalytic activity of EZH2. RD cell proliferation and myogenic differentiation were evaluated both in vitro and in vivo. RESULTS: Here we show that EZH2 protein was abnormally expressed in 19 out of 19 (100%) embryonal RMS primary tumors and cell lines compared to their normal counterparts. Genetic down-regulation of EZH2 by silencing in GM condition reduced RD cell proliferation up-regulating p21Cip1. It also resulted in myogenic-like differentiation testified by the up-regulation of myogenic markers Myogenin, MCK and MHC. These effects were reverted by enforced over-expression of a murine Ezh2, highlighting an EZH2-specific effect. Pharmacological inhibition of EZH2 using either DZNep or MC inhibitors phenocopied the genetic knockdown of EZH2 preventing cell proliferation and restoring myogenic differentiation both in vitro and in vivo. CONCLUSIONS: These results provide evidence that EZH2 function can be counteracted by pharmacological inhibition in embryonal RMS blocking proliferation even in a pro-proliferative context. They also suggest that this approach could be exploited as a differentiation therapy in adjuvant therapeutic intervention for embryonal RMS.

[Hypothyroidism incidence after multimodal treatment for laryngeal cancer]. / Incidencia de hipotiroidismo secundario a tratamiento multimodal en cáncer de laringe.

BACKGROUND: Hypothyroidism following total laryngectomy or radiotherapy treatment for laryngeal cancer is not a rare event, especially in advanced stages. There are no reports on the incidence of hypothyroidism in patients who received chemotherapy and radiotherapy. The objective of this study is to determine the incidence of thyroid dysfunction in a group of patients with laryngeal cancer who underwent surgery as sole treatment, total laryngectomy or radiotherapy alone, and patients with combined treatment: surgery plus radiotherapy, concomitant chemoradiation therapy and chemoradiation therapy plus salvage surgery. METHODS: A prospective study of patients diagnosed with laryngeal cancer whose serum TSH and T4 levels were evaluated in a serial fashion. RESULTS: 70 patients with laryngeal cancer were studied; the average age at diagnosis was 70.2 years. Male patients were more affected, with a men-women ratio of 3.6:1. Glottic localization was the most frequent (44%). 64% of tumors were locally advanced carcinomas and 51% received multimodal treatment. 45 patients (63%) were diagnosed with hypothyroidism; 49% of the patients with subclinical hypothyroidism, and 51% with clinical hypothyroidism. CONCLUSIONS: Hypothyroidism is a complication following treatment for laryngeal cancer. It is recommended to evaluate the thyroid function periodically for timely detection.

Selective control of Pax7 expression by TNF-activated p38α/polycomb repressive complex 2 (PRC2) signaling during muscle satellite cell differentiation.

Muscle regeneration relies on adult muscle stem (satellite) cells. Inflammatory cues released within the regenerative microenvironment, such as TNFα, instruct different components of the satellite cell niche toward specialized tasks by regulating specific subsets of genes in each individual cell type. However, how regeneration cues are deciphered and interpreted by the multitude of cell types within the regenerative environment is unknown. We have recently identified an inflammation-activated signaling, consisting of p38α-mediated recruitment of polycomb repressive complex 2 (PRC2) to the Pax7 promoter, in satellite cells. Here we show that p38α-PRC2 regulation of Pax7 expression is restricted to a discrete stage of satellite cell-mediated regeneration. In activated satellite cells, Pax7 locus shows a "bivalent" chromatin signature, with co-existence of H3-K27(3me) and H3-K4(3me), that appears to confer responsiveness to p38α-PRC2 signaling. p38α activation resolves bivalence to H3-K27(3me) which results in Pax7 repression, while p38α blockade promotes Pax7 expression by preventing PRC2-mediated H3-K27(3me) and leading to relative increase in H3-K4(3me). Interestingly, in satellite cell-derived myotubes Pax7 expression cannot be re-induced by p38α blockade, revealing a post-mitotic resistance of Pax7 gene to inflammatory cues. Likewise, in other cell types, such as muscle-derived fibroblasts, Pax7 locus is constitutively repressed by PRC2 and is unresponsive to p38α signaling. Finally, we show that Pax7 repression in embryonic stem cells is not directed by p38α signaling, although it is mediated by PRC2. This evidence indicates a cell type- and differentiation-stage specific control of Pax7 transcription by the p38α-PRC2.

TNF/p38α/polycomb signaling to Pax7 locus in satellite cells links inflammation to the epigenetic control of muscle regeneration.

How regeneration cues are converted into the epigenetic information that controls gene expression in adult stem cells is currently unknown. We identified an inflammation-activated signaling in muscle stem (satellite) cells, by which the polycomb repressive complex 2 (PRC2) represses Pax7 expression during muscle regeneration. TNF-activated p38α kinase promotes the interaction between YY1 and PRC2, via threonine 372 phosphorylation of EZH2, the enzymatic subunit of the complex, leading to the formation of repressive chromatin on Pax7 promoter. TNF-α antibodies stimulate satellite cell proliferation in regenerating muscles of dystrophic or normal mice. Genetic knockdown or pharmacological inhibition of the enzymatic components of the p38/PRC2 signaling--p38α and EZH2--invariably promote Pax7 expression and expansion of satellite cells that retain their differentiation potential upon signaling resumption. Genetic knockdown of Pax7 impaired satellite cell proliferation in response to p38 inhibition, thereby establishing the biological link between p38/PRC2 signaling to Pax7 and satellite cell decision to proliferate or differentiate.

Functional interdependence at the chromatin level between the MKK6/p38 and IGF1/PI3K/AKT pathways during muscle differentiation.

During muscle regeneration, the mechanism integrating environmental cues at the chromatin of muscle progenitors is unknown. We show that inflammation-activated MKK6-p38 and insulin growth factor 1 (IGF1)-induced PI3K/AKT pathways converge on the chromatin of muscle genes to target distinct components of the muscle transcriptosome. p38 alpha/beta kinases recruit the SWI/SNF chromatin-remodeling complex; AKT1 and 2 promote the association of MyoD with p300 and PCAF acetyltransferases, via direct phosphorylation of p300. Pharmacological or genetic interference with either pathway led to partial assembly of discrete chromatin-bound complexes, which reflected two reversible and distinct cellular phenotypes. Remarkably, PI3K/AKT blockade was permissive for chromatin recruitment of MEF2-SWI/SNF complex, whose remodeling activity was compromised in the absence of MyoD and acetyltransferases. The functional interdependence between p38 and IGF1/PI3K/AKT pathways was further established by the evidence that blockade of AKT chromatin targets was sufficient to prevent the activation of the myogenic program triggered by deliberate activation of p38 signaling.