Development of adenoviral vectors armed with TNF-related therapeutic proteins for gene therapy

Gene therapy has enthralled scientists in the last forty years due to its possibility of treating diseases at their genetic origin. The treatment is achieved by delivering genetic material into the patient cells via vectors (e.g., adenovirus). Through the years, several gene therapies have been developed to treat monogenic diseases (e.g., spinal muscular atrophy [SMA], adenosine deaminase deficiency [ADA]), infectious diseases (e.g., HIV/AIDS, COVID-19), cancer, among others. Fundamentally, cancer is a genetic disease that has apoptosis evasion and continuous proliferative signaling as main hallmarks. Over the years, the search for new cancer therapeutic proteins with lesser side effects than conventional chemotherapeutic drugs brought to the spotlight the apoptosis-inducing ligands from the tumor necrosis factor (TNF) family, such as TNF-, FasL, and the TNF-related apoptosis-inducing ligand (TRAIL). TRAIL is a protein that is able to selectively induces apoptosis in cancer cells while sparing the healthy cells. Another interesting member from the TNF family with potential therapeutic effects is the receptor activator of NF-B ligand (RANKL). Together with its receptors RANK and OPG due to their involvement in cancer cell migration, including their possible association to fibrosis. This thesis aims to develop adenoviral vectors armed with TRAIL and RANKL proteins for their use as treatments for cancer or fibrosis

Apoptosis-Inducing TNF Superfamily Ligands for Cancer Therapy

Cancer is a complex disease with apoptosis evasion as one of its hallmarks; therefore, apoptosis induction in transformed cells seems a promising approach as a cancer treatment. TNF apoptosis-inducing ligands, which are naturally present in the body and possess tumoricidal activity, are attractive candidates. The most studied proteins are TNF-α, FasL, and TNF-related apoptosis-inducing ligand (TRAIL). Over the years, different recombinant TNF family-derived apoptosis-inducing ligands and agonists have been designed. Their stability, specificity, and half-life have been improved because most of the TNF ligands have the disadvantages of having a short half-life and affinity to more than one receptor. Here, we review the outlook on apoptosis-inducing ligands as cancer treatments in diverse preclinical and clinical stages and summarize strategies of overcoming their natural limitations to improve their effectiveness

Galectin‐3 in venous thrombosis: A possible new target for improved patient care

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/143719/1/rth212087_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143719/2/rth212087.pd

Improvements In Cardinal, Ordinal, And Spatial Language In Young Children

Language is an important aspect of child development. Cardinal number words such as one, two, and three emerge before ordinal number words such as first, second, and third, though both increase with age in early childhood (Colomé & Noel, 2012). Children first learn verbal lists of number words, then they are able to give those words meaning (Slusser, Ditta, & Sarnecka, 2013). The more number words children know, the greater their ordinal comprehension (Brannon & Van de Walle, 2001). When children are less familiar with ordinal labels, it can negatively impact problem solving (Miller, Marcovitch, Boseovski, & Lewowicz, 2015). Spatial language also improves from 3 to 5 years and helps with problem solving (Hund, Bianchi, Winner, & Hesson-Mcinnis, 2017; Simms & Genter, 2019). Our goal was to specify the developmental trajectory of cardinal, ordinal, and spatial language comprehension and production for 3- to 5- year old children. Children were randomly assigned to either the Tell Me or Give Me condition. In the Tell Me condition, children were asked to tell the researcher about an indicated car, testing language production; whereas, in the Give Me condition, children were asked to respond to our labels by putting the appropriate car(s) in the garage, testing language comprehension. All children completed cardinal, ordinal, and spatial trials in counterbalanced order. Cardinal trials included cardinal numeric words, such as one or three. Ordinal trials included sequential numeric words, such as first or third. Spatial trials probed locations, such as front, middle, or back. To date, 65 children have participated. Data collection has not been possible during the Covid-19 pandemic. As predicted, preliminary analyses revealed that there were significant improvements across development in cardinal, ordinal, and spatial language. Five-year-olds (M = .76, SE = .05) were significantly more accurate than were 4-year-olds (M = .59, SE = .03), who were significantly more accurate than 3-year-olds (M = .46, SE = .04). In addition, the Give Me group performed higher than the Tell Me group, suggesting comprehension may be easier than production. Children were significantly more accurate on cardinal trials (M = .87, SE = .03) than on spatial trials (M = .58, SE = .04) and on spatial trials than on ordinal trials (M = .36, SE = .04). Once completed, the results of this study may be helpful for understanding the ways in which complex language facilitates developmental success across domains.https://ir.library.illinoisstate.edu/urs2021psych/1000/thumbnail.jp

La interoperabilidad en el marco de la modernización del Estado: El caso de una institución pública de Lima – 2023

La presente investigación se centró en el caso de una Institución Pública de Lima – 2023, analizando cuan efectiva es la interoperabilidad, teniendo como referente a la Modernización del Estado. Se utilizó una metodología de tipo básica, con enfoque cualitativo y con diseño de estudio de caso, en donde se tuvo fuentes documentales sobre la interoperabilidad y la modernización del Estado y como participantes a administrativos y servidores públicos que laboran en una Institución pública relacionada con el transporte; y para ahondar más en la realización del estudio, se llevaron a cabo entrevistas, elaborándose el instrumento debidamente validado para su aplicación. Se concluye que, la efectividad de la interoperabilidad en el marco de la Modernización del Estado en el caso de una Institución pública de Lima – 2023, desde las tecnologías de la información tiene una efectividad favorable, pues permite el intercambio de información, para una mejor interacción y comunicación entre las instituciones, lo que genera óptimos, seguros y céleres servicios a los ciudadanos, consiguiendo generar ahorro, transparencia y eficiencia en la gestión pública y el gobierno abierto

Moderasi Beragama di Media Sosial: Narasi Inklusivisme dalam Dakwah

This paper provides an explanation about the phenomena of religious moderation in social media. There is a tendency of new trend in religious phenomena amongst Indonesian millennial generation in this disruptive era. They are showing an interest on learn more about religion virtually. The easiness in accessing information is in a perfect proportion with the convenience of the information provider to share various kind of information, such as a religious content shared by ulama, or commonly known as dakwah. The approach of this paper is inclusivism theory on religious moderation. Religious moderation is considered as a relevant effort to cope with various kind of religious literacy on both sides, the preacher and the people, or internet user. The attempt on familiarization of the religious motion and naration can be done trough an inclusive dakwah. The result shows that there is a conceptional connection between virtual dakwah and religious moderation. There is also a diret connection between Virtual dakwah through social media and the spirit of inclusivism, that later become the main support of religious moderation. The attempt on familiarization of the religious motion and naration can also be done by religious figures and leaders with the messages of inclusivsm through virtual dakwah

Inventario sobre el deseo de tener un hijo: una aproximación desde la teoría de acción razonada

El presente estudio tuvo por objetivo la construcción y validación de un instrumento capaz de identificar el deseo de tener un hijo en mujeres adolescentes, basado en los elementos de la teoría de acción razonada. Participaron 200 adolescentes de 12 a 15 años de edad, habitantes del Estado de México (México). La versión final del instrumento tuvo una estructura mixta (diferencial semántico y escala Likert) con un total de 72 reactivos. La confiabilidad y validez mostraron que los reactivos discriminaron con un valor de p 0.007, obteniéndose un alfa de Cronbach de 0.92, KMO de 0.778 y varianza explicada de 71.79%, siendo la actitud hacia el embarazo el elemento de la mencionada teoría que mejor predice el deseo de tener un hijo. Los autores concluyen que el instrumento es válido y confiable en cuanto a su objetivo se refiere

Physiological Benefits and Performance of Sea Water Ingestion for Athletes in Endurance Events: A Systematic Review

In different endurance events, athletes have limited access to fluid intake, such as ultraendurance running. For this reason, it is necessary to establish an adequate hydration strategy for this type of long-duration sporting event. Indeed, it seems that the intake of seawater is a suitable hydration alternative to improve post-exercise recovery in this type of endurance event. This seawater is characterized by being a deep natural mineral water of moderate mineralization, which is usually extracted from a depth of about 700 m. Therefore, the aim of this systematic review is to evaluate the efficacy of seawater consumption in both performance and post-exercise recovery in long-duration sport events. A systematic and comprehensive literature search was performed in PubMed, Scopus, andWeb of Science in September 2022. Initially, 8 out of 558 articles met the inclusion criteria. Among these eight studies, six were randomized clinical trials, and two were observational studies (one cross-sectional and one prospective study in well-conditioned student athletes). The results showed that deep sea water consumption accelerated the recovery of aerobic capacity and leg muscle capacity on running performance. In addition, the lactate production after the running exercise in seawater was significantly lower than in pure water. In conclusion, the present review demonstrates that seawater consumption could significantly improve the capacity of recovery after exercise."Fundacion Ramon Areces", Madrid, SpainConsejo Nacional de Ciencia y Tecnologia (CONACyT) 218582/47197

CRISPR-mediated ablation of overexpressed EGFR in combination with sunitinib significantly suppresses renal cell carcinoma proliferation

Receptor tyrosine kinases, such as VEGFR, PDGFR and EGFR, play important roles in renal cancer. In this study, we investigated EGFR knockout as a therapeutic approach in renal cell carcinoma (RCC). We showed that a renal cell carcinoma cell line (RC21) has higher expression of EGFR as compared to other frequently used cell lines such as HEK293, A549, Hela and DLD1. Ablation of EGFR by CRISPR/Cas9 significantly restrained tumor cell growth and activated the MAPK (pERK1/2) pathway. The VEGFR and PDGFR inhibitor, sunitinib, attenuated the expression of MAPK (pERK1/2) and pAKT induced by EGFR loss and further inhibited EGFR(-/-) cell proliferation. We showed that loss of EGFR eventually leads to resistance to SAHA and cisplatin. Furthermore, EGFR loss induced G2/M phase arrest and resulted in an increased resistance to TNF-related apoptosis-inducing ligand (TRAIL) in renal cell carcinoma. Thus, ablation of overexpressed EGFR by CRISPR/Cas9 alone or in combination with sunitinib may be a new treatment option for renal cell carcinoma