Abiotic Stress Tolerance Boosted by Genetic Diversity in Plants.

Plant breeding [...].

The pharmacoepigenetic paradigm in cancer treatment.

Epigenetic modifications, characterized by changes in gene expression without altering the DNA sequence, play a crucial role in the development and progression of cancer by significantly influencing gene activity and cellular function. This insight has led to the development of a novel class of therapeutic agents, known as epigenetic drugs. These drugs, including histone deacetylase inhibitors, histone acetyltransferase inhibitors, histone methyltransferase inhibitors, and DNA methyltransferase inhibitors, aim to modulate gene expression to curb cancer growth by uniquely altering the epigenetic landscape of cancer cells. Ongoing research and clinical trials are rigorously evaluating the efficacy of these drugs, particularly their ability to improve therapeutic outcomes when used in combination with other treatments. Such combination therapies may more effectively target cancer and potentially overcome the challenge of drug resistance, a significant hurdle in cancer therapy. Additionally, the importance of nutrition, inflammation control, and circadian rhythm regulation in modulating drug responses has been increasingly recognized, highlighting their role as critical modifiers of the epigenetic landscape and thereby influencing the effectiveness of pharmacological interventions and patient outcomes. Epigenetic drugs represent a paradigm shift in cancer treatment, offering targeted therapies that promise a more precise approach to treating a wide spectrum of tumors, potentially with fewer side effects compared to traditional chemotherapy. This progress marks a step towards more personalized and precise interventions, leveraging the unique epigenetic profiles of individual tumors to optimize treatment strategies.

Gastric cancer actionable genomic alterations across diverse populations worldwide and pharmacogenomics strategies based on precision oncology.

Introduction: Gastric cancer is one of the most prevalent types of cancer worldwide. The World Health Organization (WHO), the International Agency for Research on Cancer (IARC), and the Global Cancer Statistics (GLOBOCAN) reported an age standardized global incidence rate of 9.2 per 100,000 individuals for gastric cancer in 2022, with a mortality rate of 6.1. Despite considerable progress in precision oncology through the efforts of international consortia, understanding the genomic features and their influence on the effectiveness of anti-cancer treatments across diverse ethnic groups remains essential. Methods: Our study aimed to address this need by conducting integrated in silico analyses to identify actionable genomic alterations in gastric cancer driver genes, assess their impact using deleteriousness scores, and determine allele frequencies across nine global populations: European Finnish, European non-Finnish, Latino, East Asian, South Asian, African, Middle Eastern, Ashkenazi Jewish, and Amish. Furthermore, our goal was to prioritize targeted therapeutic strategies based on pharmacogenomics clinical guidelines, in silico drug prescriptions, and clinical trial data. Results: Our comprehensive analysis examined 275,634 variants within 60 gastric cancer driver genes from 730,947 exome sequences and 76,215 whole-genome sequences from unrelated individuals, identifying 13,542 annotated and predicted oncogenic variants. We prioritized the most prevalent and deleterious oncogenic variants for subsequent pharmacogenomics testing. Additionally, we discovered actionable genomic alterations in the ARID1A, ATM, BCOR, ERBB2, ERBB3, CDKN2A, KIT, PIK3CA, PTEN, NTRK3, TP53, and CDKN2A genes that could enhance the efficacy of anti-cancer therapies, as suggested by in silico drug prescription analyses, reviews of current pharmacogenomics clinical guidelines, and evaluations of phase III and IV clinical trials targeting gastric cancer driver proteins. Discussion: These findings underline the urgency of consolidating efforts to devise effective prevention measures, invest in genomic profiling for underrepresented populations, and ensure the inclusion of ethnic minorities in future clinical trials and cancer research in developed countries.

Transcaval approach for aortic endoprosthesis insertion. A new anesthetic challenge.

The treatment of acute aortic syndrome has been benefited in recent years from the huge progress in endovascular techniques, compared to classical surgical treatment, by open surgery. Nevertheless, for endovascular treatment to be successful, it is essential for the patient to present adequate vascular access. Those cases with unfavourable vascular anatomy make it necessary to consider open surgery with significant morbidity, or even to reject surgery. A new approach to the abdominal aorta has recently been described as an indication for these patients with impossibility of other vascular access and absolute or relative contraindication to the transthoracic approach. The anesthetic management of the aortic syndrome is well known and, even though there are a variety of options, all of them have proven safety and efficacy. The implementation of new surgical approaches and new possible complications imply a challenge for the anesthesiologist which, for now, has little or none scientific evidence. We present the first case of transcaval aortic endoprosthesis implantation in Spain, its anesthetic implications, and a review of the literature.

Toward Equitable Precision Oncology: Monitoring Racial and Ethnic Inclusion in Genomics and Clinical Trials.

PURPOSE: Ethnic diversity in cancer research is crucial as race/ethnicity influences cancer incidence, survival, drug response, molecular pathways, and epigenetic phenomena. In 2018, we began a project to examine racial/ethnic diversity in cancer research, with a commitment to review these disparities every 4 years. This report is our second assessment, detailing the present state of racial/ethnic diversity in cancer genomics and clinical trials. METHODS: To study racial/ethnic inclusion in cancer genomics, we extracted ethnic records from all data sets available at cBioPortal (n = 125,128 patients) and cancer-related genome-wide association studies (n = 28,011,282 patients) between 2018 and 2022. Concerning clinical trials, we selected studies related to breast cancer (n = 125,518 patients, 181 studies), lung cancer (n = 34,329 patients, 119 studies), and colorectal cancer (n = 40,808 patients, 105 studies). RESULTS: In cancer genomics (N = 28,136,410), 3% of individuals lack racial/ethnic registries; tumor samples were collected predominantly from White patients (89.14%), followed by Asian (7%), African American (0.55%), and Hispanic (0.21%) patients and other populations (0.1%). In clinical trials (N = 200,655), data on race/ethnicity are missing for 60.14% of the participants; for individuals whose race/ethnicity was recorded, most were characterized as White (28.33%), followed by Asian (7.64%), African (1.79), other ethnicities (1.37), and Hispanic (0.73). Racial/ethnic representation significantly deviates from global ethnic proportions (P ≤ .001) across all data sets, with White patients outnumbering other ethnic groups by a factor of approximately 4-6. CONCLUSION: Our second update on racial/ethnic representation in cancer research highlights the persistent overrepresentation of White populations in cancer genomics and a notable absence of racial/ethnic information across clinical trials. To ensure more equitable and effective precision oncology, future efforts should address the reasons behind the insufficient representation of ethnically diverse populations in cancer research.

CardiOmics signatures reveal therapeutically actionable targets and drugs for cardiovascular diseases.

Cardiovascular diseases are the leading cause of death worldwide, with heart failure being a complex condition that affects millions of individuals. Single-nucleus RNA sequencing has recently emerged as a powerful tool for unraveling the molecular mechanisms behind cardiovascular diseases. This cutting-edge technology enables the identification of molecular signatures, intracellular networks, and spatial relationships among cardiac cells, including cardiomyocytes, mast cells, lymphocytes, macrophages, lymphatic endothelial cells, endocardial cells, endothelial cells, epicardial cells, adipocytes, fibroblasts, neuronal cells, pericytes, and vascular smooth muscle cells. Despite these advancements, the discovery of essential therapeutic targets and drugs for precision cardiology remains a challenge. To bridge this gap, we conducted comprehensive in silico analyses of single-nucleus RNA sequencing data, functional enrichment, protein interactome network, and identification of the shortest pathways to physiological phenotypes. This integrated multi-omics analysis generated CardiOmics signatures, which allowed us to pinpoint three therapeutically actionable targets (ADRA1A1, PPARG, and ROCK2) and 15 effective drugs, including adrenergic receptor agonists, adrenergic receptor antagonists, norepinephrine precursors, PPAR receptor agonists, and Rho-associated kinase inhibitors, involved in late-stage cardiovascular disease clinical trials.

Biological role of fructose in the male reproductive system: Potential implications for prostate cancer.

BACKGROUND: Over the last 20 years, fructose has gradually emerged as a potential metabolic substrate capable of promoting the growth and progression of various cancers, including prostate cancer (PCa). The biological and molecular mechanisms that underlie the effects of fructose on cancer are beginning to be elucidated. METHODS: This review summarizes the biological function of fructose as a potential carbon source for PCa cells and its role in the functionality of the male reproductive tract under normal conditions. RESULTS: The most recent biological advances related to fructose transport and metabolism as well as their implications in PCa growth and progression suggest that fructose represent a potential carbon source for PCa cells. Consequently, fructose derivatives may represent efficient radiotracers for obtaining PCa images via positron emission tomography and fructose transporters/fructose-metabolizing enzymes could be utilized as potential diagnostic and/or predictive biomarkers for PCa. CONCLUSION: The existing data suggest that restriction of fructose from the diet could be a useful therapeutic strategy for patients with PCa.

Population-Specific Distribution of TPMT Deficiency Variants and Ancestry Proportions in Ecuadorian Ethnic Groups: Towards Personalized Medicine.

Purpose: Thiopurine S-methyltransferase (TPMT) is an enzyme that metabolizes purine analogs, agents used in the treatment of acute lymphoblastic leukemia. Improper drug metabolism leads to toxicity in chemotherapy patients and reduces treatment effectiveness. TPMT variants associated with reduced enzymatic activity vary across populations. Therefore, studying these variants in heterogeneous populations, such as Ecuadorians, can help identify molecular causes of deficiency for this enzyme. Methods: We sequenced the entire TPMT coding region in 550 Ecuadorian individuals from Afro-Ecuadorian, Indigenous, Mestizo, and Montubio ethnicities. Moreover, we conducted an ancestry analysis using 46 informative ancestry markers. Results: We identified 8 single nucleotide variants in the coding region of TPMT. The most prevalent alleles were TPMT*3A, TPMT*3B, and TPMT*3C, with frequencies of 0.055, 0.012, and 0.015, respectively. Additionally, we found rare alleles TPMT*4 and TPMT*8 with frequencies of 0.005 and 0.003. Correlating the ancestry proportions with TPMT-deficient genotypes, we observed that the Native American ancestry proportion influenced the distribution of the TPMT*1/TPMT*3A genotype (OR = 5.977, p = 0.002), while the contribution of African ancestral populations was associated with the TPMT*1/TPMT*3C genotype (OR = 9.769, p = 0.003). The rates of TPMT-deficient genotypes observed in Mestizo (f = 0.121) and Indigenous (f = 0.273) groups provide evidence for the influence of Native American ancestry and the prevalence of the TPMT*3A allele. In contrast, although Afro-Ecuadorian groups demonstrate similar deficiency rates (f = 0.160), the genetic factors involved are associated with contributions from African ancestral populations, specifically the prevalent TPMT*3C allele. Conclusion: The distribution of TPMT-deficient variants offers valuable insights into the populations under study, underscoring the necessity for genetic screening strategies to prevent thiopurine toxicity events among Latin American minority groups.

Genetic basis and spatial distribution of glucose-6-phosphate dehydrogenase deficiency in ecuadorian ethnic groups: a malaria perspective.

BACKGROUND: Glucose-6-phosphate dehydrogenase deficiency (G6PDd) is an X-linked disorder affecting over 400 million people worldwide. Individuals with molecular variants associated with reduced enzymatic activity are susceptible to oxidative stress in red blood cells, thereby increasing the risk of pathophysiological conditions and toxicity to anti-malarial treatments. Globally, the prevalence of G6PDd varies among populations. Accordingly, this study aims to characterize G6PDd distribution within the Ecuadorian population and to describe the spatial distribution of reported malaria cases. METHODS: Molecular variants associated with G6PDd were genotyped in 581 individuals from Afro-Ecuadorian, Indigenous, Mestizo, and Montubio ethnic groups. Additionally, spatial analysis was conducted to identify significant malaria clusters with high incidence rates across Ecuador, using data collected from 2010 to 2021. RESULTS: The A- c.202G > A and A- c.968T > C variants underpin the genetic basis of G6PDd in the studied population. The overall prevalence of G6PDd was 4.6% in the entire population. However, this frequency increased to 19.2% among Afro-Ecuadorian people. Spatial analysis revealed 12 malaria clusters, primarily located in the north of the country and its Amazon region, with relative risks of infection of 2.02 to 87.88. CONCLUSIONS: The findings of this study hold significant implications for public health interventions, treatment strategies, and targeted efforts to mitigate the burden of malaria in Ecuador. The high prevalence of G6PDd among Afro-Ecuadorian groups in the northern endemic areas necessitates the development of comprehensive malaria eradication strategies tailored to this geographical region.

Integrated multi-omics analysis reveals the molecular interplay between circadian clocks and cancer pathogenesis.

Circadian rhythms (CRs) are fundamental biological processes that significantly impact human well-being. Disruption of these rhythms can trigger insufficient neurocognitive development, insomnia, mental disorders, cardiovascular diseases, metabolic dysfunctions, and cancer. The field of chronobiology has increased our understanding of how rhythm disturbances contribute to cancer pathogenesis, and how circadian timing influences the efficacy of cancer treatments. As the circadian clock steadily gains recognition as an emerging factor in tumorigenesis, a thorough and comprehensive multi-omics analysis of CR genes/proteins has never been performed. To shed light on this, we performed, for the first time, an integrated data analysis encompassing genomic/transcriptomic alterations across 32 cancer types (n = 10,918 tumors) taken from the PanCancer Atlas, unfavorable prognostic protein analysis, protein-protein interactomics, and shortest distance score pathways to cancer hallmark phenotypes. This data mining strategy allowed us to unravel 31 essential CR-related proteins involved in the signaling crossroad between circadian rhythms and cancer. In the context of drugging the clock, we identified pharmacogenomic clinical annotations and drugs currently in late phase clinical trials that could be considered as potential cancer therapeutic strategies. These findings highlight the diverse roles of CR-related genes/proteins in the realm of cancer research and therapy.

An 11-year epidemiological analysis of schistosomiasis in Ecuador: Investigating a non-endemic, neglected, and challenging-to-identify parasitic disease.

Schistosomiasis is a neglected disease caused by parasites of the genus Schistosoma and transmitted by snails of the genus Biomphalaria. At least five species have the potential to infect humans living in or visiting tropical areas worldwide. In Latin America, Schistosoma mansoni is particularly common; however, it has not been reported in Ecuador. In this study, we assess the available official data on schistosomiasis in Ecuador to describe the prevalence of this neglected disease. We conducted a nationwide study to determine the demographic and spatial distribution patterns of schistosomiasis infection in Ecuador, using hospital discharge official data as a proxy for infection incidence from 2011 to 2021. We calculated crude and age-sex-adjusted morbidity and hospital admission rates by region, province, canton, and elevation. In the last decade of available data, schistosomiasis accounted for at least 551 hospital admissions in Ecuador. Women represented 53.7% (n = 296) of cases, equivalent to 3.2 cases per 1,000,000 inhabits. The highest number of cases (61.2%, n = 337) was found in the Coastal region. However, the highest incidence rates were observed in the Amazon region's provinces of Pastaza (173.44 cases/1,000,000).

Data mining identifies novel RNA-binding proteins involved in colon and rectal carcinomas.

Colorectal adenocarcinoma (COREAD) is the second most deadly cancer and third most frequently encountered malignancy worldwide. Despite efforts in molecular subtyping and subsequent personalized COREAD treatments, multidisciplinary evidence suggests separating COREAD into colon cancer (COAD) and rectal cancer (READ). This new perspective could improve diagnosis and treatment of both carcinomas. RNA-binding proteins (RBPs), as critical regulators of every hallmark of cancer, could fulfill the need to identify sensitive biomarkers for COAD and READ separately. To detect new RBPs involved in COAD and READ progression, here we used a multidata integration strategy to prioritize tumorigenic RBPs. We analyzed and integrated 1) RBPs genomic and transcriptomic alterations from 488 COAD and 155 READ patients, 2) ∼ 10,000 raw associations between RBPs and cancer genes, 3) ∼ 15,000 immunostainings, and 4) loss-of-function screens performed in 102 COREAD cell lines. Thus, we unraveled new putative roles of NOP56, RBM12, NAT10, FKBP1A, EMG1, and CSE1L in COAD and READ progression. Interestingly, FKBP1A and EMG1 have never been related with any of these carcinomas but presented tumorigenic features in other cancer types. Subsequent survival analyses highlighted the clinical relevance of FKBP1A, NOP56, and NAT10 mRNA expression to predict poor prognosis in COREAD and COAD patients. Further research should be performed to validate their clinical potential and to elucidate their molecular mechanisms underlying these malignancies.

Molecular Genetics Enhances Plant Breeding.

Human-driven plant selection, a practice as ancient as agriculture itself, has laid the foundations of plant breeding and contemporary farming [...].

An updated examination of the perception of barriers for pharmacogenomics implementation and the usefulness of drug/gene pairs in Latin America and the Caribbean.

Pharmacogenomics (PGx) is considered an emergent field in developing countries. Research on PGx in the Latin American and the Caribbean (LAC) region remains scarce, with limited information in some populations. Thus, extrapolations are complicated, especially in mixed populations. In this paper, we reviewed and analyzed pharmacogenomic knowledge among the LAC scientific and clinical community and examined barriers to clinical application. We performed a search for publications and clinical trials in the field worldwide and evaluated the contribution of LAC. Next, we conducted a regional structured survey that evaluated a list of 14 potential barriers to the clinical implementation of biomarkers based on their importance. In addition, a paired list of 54 genes/drugs was analyzed to determine an association between biomarkers and response to genomic medicine. This survey was compared to a previous survey performed in 2014 to assess progress in the region. The search results indicated that Latin American and Caribbean countries have contributed 3.44% of the total publications and 2.45% of the PGx-related clinical trials worldwide thus far. A total of 106 professionals from 17 countries answered the survey. Six major groups of barriers were identified. Despite the region's continuous efforts in the last decade, the primary barrier to PGx implementation in LAC remains the same, the "need for guidelines, processes, and protocols for the clinical application of pharmacogenetics/pharmacogenomics". Cost-effectiveness issues are considered critical factors in the region. Items related to the reluctance of clinicians are currently less relevant. Based on the survey results, the highest ranked (96%-99%) gene/drug pairs perceived as important were CYP2D6/tamoxifen, CYP3A5/tacrolimus, CYP2D6/opioids, DPYD/fluoropyrimidines, TMPT/thiopurines, CYP2D6/tricyclic antidepressants, CYP2C19/tricyclic antidepressants, NUDT15/thiopurines, CYP2B6/efavirenz, and CYP2C19/clopidogrel. In conclusion, although the global contribution of LAC countries remains low in the PGx field, a relevant improvement has been observed in the region. The perception of the usefulness of PGx tests in biomedical community has drastically changed, raising awareness among physicians, which suggests a promising future in the clinical applications of PGx in LAC.

Mental Health of People Under Isolation During the covm-19 Outbreak: An Exploratory Study Running head: Psychological health and isolation during COVID-19 / La Salud Mental de Personas en Aislamiento Durante el Brote De COVID-19: Estudio Exploratorio Salud mental y aislamiento durante el COVID-19

Abstract We conducted an exploratory study using a survey inquiring on seven topics on how people were reacting to the co-viD-19 pandemic of 2020 aiming to trace a map of symptoms and feelings related to mental health and isolation. 1785 people participated in the survey. Additionally, we applied two psychological scales to analyze depression and stress (prevalent in previous studies). We found that people in isolation during the pandemic presented symptoms related to dissociative disorders, negative affect, and anxiety syndrome. Also, depression and stress had a high prevalence compared to the average rates indicated by the World Health Organisation and the Colombian Ministry of Health. The results indicated an association between depression and stress and being previously diagnosed with a mental health problem, and job and financial situation. Our results highlight the need to design prevention and intervention programmes to reduce the negative consequences of isolation.

Resumen Realizamos un estudio exploratorio utilizando un cuestionario sobre siete temas acerca de cómo las personas reaccionaron a la pandemia del COVID-19 de 2020 con el objetivo de trazar un mapa de los síntomas y sentimientos relacionados con la salud mental y el aislamiento. En la encuesta participaron 1785 personas. Además, aplicamos dos escalas psicológicas para analizar la depresión y el estrés (prevalente en estudios anteriores). Encontramos que las personas aisladas durante la pandemia presentaban síntomas relacionados con trastornos disociativos, afectos negativos y síndrome de ansiedad. Además, la depresión y el estrés tuvieron una alta prevalencia en comparación con las tasas promedio indicadas por la Organización Mundial de la Salud y el Ministerio de Salud de Colombia. Los resultados indicaron una asociación entre la depresión, el estrés y ser diagnosticado previamente con un problema de salud mental y la situación laboral y financiera. Nuestros resultados ponen de relieve la necesidad de disenar programas de prevención e intervención para reducir las consecuencias negativas del aislamiento.

Genome-Environment Associations, an Innovative Tool for Studying Heritable Evolutionary Adaptation in Orphan Crops and Wild Relatives.

Leveraging innovative tools to speed up prebreeding and discovery of genotypic sources of adaptation from landraces, crop wild relatives, and orphan crops is a key prerequisite to accelerate genetic gain of abiotic stress tolerance in annual crops such as legumes and cereals, many of which are still orphan species despite advances in major row crops. Here, we review a novel, interdisciplinary approach to combine ecological climate data with evolutionary genomics under the paradigm of a new field of study: genome-environment associations (GEAs). We first exemplify how GEA utilizes in situ georeferencing from genotypically characterized, gene bank accessions to pinpoint genomic signatures of natural selection. We later discuss the necessity to update the current GEA models to predict both regional- and local- or micro-habitat-based adaptation with mechanistic ecophysiological climate indices and cutting-edge GWAS-type genetic association models. Furthermore, to account for polygenic evolutionary adaptation, we encourage the community to start gathering genomic estimated adaptive values (GEAVs) for genomic prediction (GP) and multi-dimensional machine learning (ML) models. The latter two should ideally be weighted by de novo GWAS-based GEA estimates and optimized for a scalable marker subset. We end the review by envisioning avenues to make adaptation inferences more robust through the merging of high-resolution data sources, such as environmental remote sensing and summary statistics of the genomic site frequency spectrum, with the epigenetic molecular functionality responsible for plastic inheritance in the wild. Ultimately, we believe that coupling evolutionary adaptive predictions with innovations in ecological genomics such as GEA will help capture hidden genetic adaptations to abiotic stresses based on crop germplasm resources to assist responses to climate change. "I shall endeavor to find out how nature's forces act upon one another, and in what manner the geographic environment exerts its influence on animals and plants. In short, I must find out about the harmony in nature" Alexander von Humboldt-Letter to Karl Freiesleben, June 1799.

Genetic Variations of the DPYD Gene and Its Relationship with Ancestry Proportions in Different Ecuadorian Trihybrid Populations.

Dihydropyrimidine dehydrogenase is one of the main pharmacological metabolizers of fluoropyrimidines, a group of drugs widely used in clinical oncology. Around 20 to 30% of patients treated with fluoropyrimidines experience severe toxicity caused by a partial or total decrease in enzymatic activity. This decrease is due to molecular variants in the DPYD gene. Their prevalence and allelic frequencies vary considerably worldwide, so their description in heterogeneous groups such as the Ecuadorian population will allow for the description of pharmacogenetic variants and proper characterization of this population. Thus, we genotyped all the molecular variants with a predictive value for DPYD in a total of 410 Ecuadorian individuals belonging to Mestizo, Afro-Ecuadorian, and Indigenous ethnic groups. Moreover, we developed a genetic ancestry analysis using 46 autosomal ancestry informative markers. We determined 20 genetic variations in 5 amplified regions, including 3 novel single nucleotide variants. The allele frequencies for DPYD variants c.1627G>A (*5, rs1801159), c.1129-15T>C (rs56293913), c.1218G>A (rs61622928), rs1337752, rs141050810, rs2786783, rs2811178, and g.97450142G>A (chr1, GRCh38.p13) are significantly related to Native American and African ancestry proportions. In addition, the FST calculated from these variants demonstrates the closeness between Indigenous and Mestizo populations, and evidences genetic divergence between Afro-Ecuadorian groups when compared with Mestizo and Indigenous ethnic groups. In conclusion, the genetic variability in the DPYD gene is related to the genetic component of ancestral populations in different Ecuadorian ethnic groups. The absence and low frequency of variants with predictive value for fluoropyrimidine toxicity such as DPYD *2A, HapB3, and c.2846A>T (prevalent in populations with European ancestry) is consistent with the genetic background found.