Childhood leukemias in Mexico: towards implementing CAR-T cell therapy programs.

Leukemias are the most common type of pediatric cancer around the world. Prognosis has improved during the last decades, and many patients are cured with conventional treatment as chemotherapy; however, many patients still present with a refractory disease requiring additional treatments, including hematopoietic stem cell transplantation. Immunotherapy with monoclonal antibodies or cellular therapy is a promising strategy for treating refractory or relapsed hematological malignancies. Particularly, CAR-T cells have shown clinical efficacy in clinical trials, and different products are now commercially approved by regulatory agencies in the USA and Europe. Many challenges still need to be solved to improve and optimize the potential of these therapies worldwide. Global access to cell therapy is a significant concern, and different strategies are being explored in the middle- and low-income countries. In Mexico, leukemias represent around 50% of total cancer diagnosed in pediatric patients, and the rate of relapsed or refractory disease is higher than reported in other countries, a multi-factorial problem. Although significant progress has been made during the last decades in leukemia diagnosis and treatment, making new therapies available to Mexican patients is a priority, and cell and gene therapies are on the horizon. Efforts are ongoing to make CAR-T cell therapy accessible for patients in Mexico. This article summarizes a general landscape of childhood leukemias in Mexico, and we give a perspective about the current strategies, advances, and challenges ahead to make gene and cell therapies for leukemia clinically available.

Capturing the Experiences and Challenges of Emerging Adults in College During the COVID-19 Pandemic.

Emerging adulthood (ages 18-30 years) coincides with "aging out" of pediatric care. As a result, combined internal medicine and pediatrics (Med-Peds) providers are tasked with promoting the health and well-being of this population during and post-coronavirus disease 2019 (COVID-19). In order to inform the response efforts, we aimed to capture emerging adults' COVID-19 experiences and challenges during a two-week period of the pandemic in June 2020. We administered items from the California Health Interview Survey and an open-ended qualitative item via Qualtrics to 242 diverse emerging adults enrolled in a large US public university (mean age = 20.10, SD = 1.26). More than 90% of all students reported that they or their families or close friends experienced difficulties coping with the stressors and challenges presented by COVID-19. Almost half experienced financial difficulties and more than three-fourths experienced household disruptions during the pandemic. Qualitative findings underscored that these challenges were compounded by mental health and broader social issues. Recommendations for Med-Peds providers are provided to promote emerging adulthood health during and post-pandemic.

Chimeric Antigen Receptor-T Cells: A Pharmaceutical Scope.

Cancer is among the leading causes of death worldwide. Therefore, improving cancer therapeutic strategies using novel alternatives is a top priority on the contemporary scientific agenda. An example of such strategies is immunotherapy, which is based on teaching the immune system to recognize, attack, and kill malignant cancer cells. Several types of immunotherapies are currently used to treat cancer, including adoptive cell therapy (ACT). Chimeric Antigen Receptors therapy (CAR therapy) is a kind of ATC where autologous T cells are genetically engineered to express CARs (CAR-T cells) to specifically kill the tumor cells. CAR-T cell therapy is an opportunity to treat patients that have not responded to other first-line cancer treatments. Nowadays, this type of therapy still has many challenges to overcome to be considered as a first-line clinical treatment. This emerging technology is still classified as an advanced therapy from the pharmaceutical point of view, hence, for it to be applied it must firstly meet certain requirements demanded by the authority. For this reason, the aim of this review is to present a global vision of different immunotherapies and focus on CAR-T cell technology analyzing its elements, its history, and its challenges. Furthermore, analyzing the opportunity areas for CAR-T technology to become an affordable treatment modality taking the basic, clinical, and practical aspects into consideration.

The Noncanonical Heat Shock Protein PvNod22 Is Essential for Infection Thread Progression During Rhizobial Endosymbiosis in Common Bean.

In the establishment of plant-rhizobial symbiosis, the plant hosts express nodulin proteins during root nodule organogenesis. A limited number of nodulins have been characterized, and these perform essential functions in root nodule development and metabolism. Most nodulins are expressed in the nodule and at lower levels in other plant tissues. Previously, we isolated Nodulin 22 (PvNod22) from a common bean (Phaseolus vulgaris L.) cDNA library derived from Rhizobium-infected roots. PvNod22 is a noncanonical, endoplasmic reticulum (ER)-localized, small heat shock protein that confers protection against oxidative stress when overexpressed in Escherichia coli. Virus-induced gene silencing of PvNod22 resulted in necrotic lesions in the aerial organs of P. vulgaris plants cultivated under optimal conditions, activation of the ER-unfolded protein response (UPR), and, finally, plant death. Here, we examined the expression of PvNod22 in common bean plants during the establishment of rhizobial endosymbiosis and its relationship with two cellular processes associated with plant immunity, the UPR and autophagy. In the RNA interference lines, numerous infection threads stopped their progression before reaching the cortex cell layer of the root, and nodules contained fewer nitrogen-fixing bacteroids. Collectively, our results suggest that PvNod22 has a nonredundant function during legume-rhizobia symbiosis associated with infection thread elongation, likely by sustaining protein homeostasis in the ER.

Uncovering Bax inhibitor-1 dual role in the legume-rhizobia symbiosis in common bean roots.

Bax-inhibitor 1 (BI-1) is a cell death suppressor conserved in all eukaryotes that modulates cell death in response to abiotic stress and pathogen attack in plants. However, little is known about its role in the establishment of symbiotic interactions. Here, we demonstrate the functional relevance of an Arabidopsis thaliana BI-1 homolog (PvBI-1a) to symbiosis between the common bean (Phaseolus vulgaris) and Rhizobium tropici. We show that the changes in expression of PvBI-1a observed during early symbiosis resemble those of some defence response-related proteins. By using gain- and loss-of-function approaches, we demonstrate that the overexpression of PvBI-1a in the roots of common bean increases the number of rhizobial infection events (and therefore the final number of nodules per root), but induces the premature death of nodule cells, affecting their nitrogen fixation efficiency. Nodule morphological alterations are known to be associated with changes in the expression of genes tied to defence, autophagy, and vesicular trafficking. Results obtained in the present work suggest that BI-1 has a dual role in the regulation of programmed cell death during symbiosis, extending our understanding of its critical function in the modulation of host immunity while responding to beneficial microbes.

Small RNAs Derived from the T-DNA of Agrobacterium rhizogenes in Hairy Roots of Phaseolus vulgaris.

Agrobacterium rhizogenes is a pathogenic bacteria that causes hairy root disease by transferring bacterial DNA into the plant genome. It is an essential tool for industry and research due to its capacity to produce genetically modified roots and whole organisms. Here, we identified and characterized small RNAs generated from the transfer DNA (T-DNA) of A. rhizogenes in hairy roots of common bean (Phaseolus vulgaris). Distinct abundant A. rhizogenes T-DNA-derived small RNAs (ArT-sRNAs) belonging to several oncogenes were detected in hairy roots using high-throughput sequencing. The most abundant and diverse species of ArT-sRNAs were those of 21- and 22-nucleotides in length. Many T-DNA encoded genes constituted phasiRNA producing loci (PHAS loci). Interestingly, degradome analysis revealed that ArT-sRNAs potentially target genes of P. vulgaris. In addition, we detected low levels of ArT-sRNAs in the A. rhizogenes-induced calli generated at the wound site before hairy root emergence. These results suggest that RNA silencing targets several genes from T-DNA of A. rhizogenes in hairy roots of common bean. Therefore, the role of RNA silencing observed in this study has implications in our understanding and usage of this unique plant-bacteria interaction.

Detailed analysis of putative genes encoding small proteins in legume genomes.

Diverse plant genome sequencing projects coupled with powerful bioinformatics tools have facilitated massive data analysis to construct specialized databases classified according to cellular function. However, there are still a considerable number of genes encoding proteins whose function has not yet been characterized. Included in this category are small proteins (SPs, 30-150 amino acids) encoded by short open reading frames (sORFs). SPs play important roles in plant physiology, growth, and development. Unfortunately, protocols focused on the genome-wide identification and characterization of sORFs are scarce or remain poorly implemented. As a result, these genes are underrepresented in many genome annotations. In this work, we exploited publicly available genome sequences of Phaseolus vulgaris, Medicago truncatula, Glycine max, and Lotus japonicus to analyze the abundance of annotated SPs in plant legumes. Our strategy to uncover bona fide sORFs at the genome level was centered in bioinformatics analysis of characteristics such as evidence of expression (transcription), presence of known protein regions or domains, and identification of orthologous genes in the genomes explored. We collected 6170, 10,461, 30,521, and 23,599 putative sORFs from P. vulgaris, G. max, M. truncatula, and L. japonicus genomes, respectively. Expressed sequence tags (ESTs) available in the DFCI Gene Index database provided evidence that ~one-third of the predicted legume sORFs are expressed. Most potential SPs have a counterpart in a different plant species and counterpart regions or domains in larger proteins. Potential functional sORFs were also classified according to a reduced set of GO categories, and the expression of 13 of them during P. vulgaris nodule ontogeny was confirmed by qPCR. This analysis provides a collection of sORFs that potentially encode for meaningful SPs, and offers the possibility of their further functional evaluation.