Lymphomas arise in any body region containing lymphatic tissue and are mainly classified into Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). This study summarizes genetic findings in Ecuadorian lymphoma patients from 1984 to the present, based on analyses from ten national centers. A total of 703 lymphomas were studied, with 12.4% HL and 87.6% NHL. Most cases occurred in males, and the most affected age group was over 60 years, consistent with global epidemiology. Genetic studies have evolved in Ecuador over the last four decades, incorporating conventional cytogenetics, fluorescence in situ hybridization (FISH), spectral karyotyping (SKY), PCR, Sanger sequencing, and Next-Generation Sequencing (NGS). Cytogenetic analysis revealed normal karyotypes in 70% of HL and 59.4% of NHL, with abnormal karyotypes in 17.6% of HL and 27.1% of NHL. FISH utilized probes for MYC, t(8;14), t(14;18), BCL2, BCL6, and TP53, supporting the identification of hallmark rearrangements. A key finding was the absence of the t(14;18) translocation in 65 NHL cases analyzed by PCR, suggesting it is rare in the Ecuadorian population, a result confirmed by FISH studies since 2012. Investigation of the hMSH2 gene variant rs2303428 in 22 NHL patients found a 22.73% frequency, suggesting an association with disease risk. A subsequent study on 87 NHL cases confirmed the finding, with a 0.09 allele frequency and significant differences from controls (p<0.01). NGS enabled the detection of rare and novel chromosomal alterations, such as the t(8;9)(q24;q33) MYC::FBXW2 fusion, not previously described in the literature. Within the Ibero-American Lymphoma Network, Ecuador reports a low incidence of follicular lymphoma, similar to other Andean countries but differing from Southern Cone nations, and clonality studies are not yet performed locally. These findings demonstrate the critical role of cytogenetic and molecular analysis in the accurate classification, treatment guidance, and follow-up of lymphoma patients. The rarity of certain rearrangements, the identification of unique genetic variants, and the growing use of advanced molecular tools highlight the importance of regional genomic studies to improve diagnosis and personalized medicine in Latin America.

Alu elements are non-autonomous Short INterspersed Elements (SINEs) derived from the 7SL RNA gene that are present at over one million copies in human genomic DNA. Alu mobilizes by a mechanism known as retrotransposition, which requires the Long INterspersed Element-1 (LINE-1 or L1) ORF2-encoded protein (ORF2p). Here, we demonstrate that HeLa strains differ in their capacity to support Alu retrotransposition. Human Alu elements retrotranspose efficiently in HeLa-HA and HeLa-CCL2 (Alu-permissive) strains, but not in HeLa-JVM or HeLa-H1 (Alu-nonpermissive) strains. A similar pattern of retrotransposition was observed for other 7SL RNA-derived SINEs and tRNA-derived SINEs. In contrast, mammalian LINE-1s, a zebrafish LINE, a human SINE-VNTR-Alu (SVA) element, and an L1 ORF1-containing messenger RNA can retrotranspose in all four HeLa strains. Using an in vitro reverse transcriptase-based assay, we show that Alu RNAs associate with ORF2p and are converted into cDNAs in both Alu-permissive and Alu-nonpermissive HeLa strains, suggesting that 7SL- and tRNA-derived SINE RNAs use strategies to hijack L1 ORF2p that are distinct from those used by SVA elements and ORF1-containing mRNAs. These data further suggest ORF2p associates with the Alu RNA poly(A) tract in both Alu-permissive and Alu-nonpermissive HeLa strains, but that Alu retrotransposition is blocked after this critical step in Alu-nonpermissive HeLa strains.

N-acetylaspartate (NAA) is an abundant central nervous system amino acid derivative that is tightly coupled to mitochondria and energy metabolism in neurons. A reduced NAA signature is a prominent early pathological biomarker in multiple neurodegenerative diseases and becomes progressively more pronounced as disease advances. Because NAA synthesis requires aspartate drawn directly from mitochondria, we argued that this process is in direct competition with oxidative phosphorylation for substrate and that sustained high levels of NAA synthesis would be incompatible with pathological energy crisis. We show here that over-expression of the rate-limiting NAA synthetic enzyme in the hippocampus of the 5x familial Alzheimer's disease (5xFAD) mouse results in an exaggerated pathological ATP deficit and accelerated cognitive decline. Over-expression of NAA synthase did not increase amyloid burden or result in cell loss but did significantly deplete mitochondrial aspartate and impair the ability of mitochondria to oxidize glutamate for adenosine triphosphate (ATP) synthesis. These results define NAA as a sink for energetic substrate and suggest initial pathological reductions in NAA are part of a response to energetic crisis designed to preserve substrate bioavailability for mitochondrial ATP synthesis.

We present the case of a 7-year-old Ecuadorian mestizo girl with multiple orofacial malformations. The patient is the product of a first-degree relationship (father–daughter). A cytogenetic study revealed a normal karyotype. The genetic mapping array study identified 0.73 Gb of alterations, 727,087,295 bp involved in regions of homozygosity (ROH) in all chromosomes (25.2

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Supplementary Figure 3 from Deficiency in p53 but not Retinoblastoma Induces the Transformation of Mesenchymal Stem Cells In vitro and Initiates Leiomyosarcoma In vivo

We present a scarce case in which three pathologies converge: XX/XY chimerism, hermaphroditism with ovotestis and situs inversus totalis. She is a patient of mixed ethnicity, with predominantly Amerindian markers, who underwent a conventional cytogenetic study, FISH and DNA study of peripheral blood (mesoderm) and buccal mucosa scraping (ectoderm), additionally X-rays, hormonal tests and biopsy of the right gonad. The patient presents hypogonadism, female hypoplastic external sexual organs, and Tanner sexual development 1-2. X-rays show situs inversus totalis. The data for female and male hormones are altered. The karyotype showed the presence of two cell populations, XX and XY, confirmed with FISH and a study of the positive SRY gene. The evaluation of the DNA by numerical Arrays verified the presence of chromosomes X and Y; in the same way, gains and losses of essential genes related to the patient's phenotype were evidenced. We performed an in silico evaluation of the interactome of proteins involved in the clinical manifestations that reflect the alterations of the corresponding genes, which allowed us to make a genotype-phenotype correlation. In conclusion, the studies with a complete clinical, laboratory and genetic panel allowed us to define its alterations. Keywords: chimerism, 46, XX/46, XY, ovotestis, situs inversus totalis

BACKGROUND:Neuroinflammation in the cerebral cortex of patients who died with liver cirrhosis and neuroinflammation, and neuronal death in the cerebellum of patients who died with steatohepatitis or cirrhosis, were reported. Hippocampal neuroinflammation could contribute to cognitive decline in patients with liver disease, but this has yet to be studied. The study aims were to assess if hippocampus from patients who died with steatohepatitis or cirrhosis showed: (i) glial activation, (ii) altered cytokine content, (iii) immune cell infiltration, (iv) neuronal apoptosis and (v) neuronal loss.METHODS:Post-mortem hippocampus was obtained from 6 controls, 19 patients with steatohepatitis (SH) and 4 patients with liver cirrhosis. SH patients were divided into SH1 (n = 9), SH2 (n = 6) and SH3 (n = 4) groups depending on disease severity. Glial activation, IL-1β and TNFα content, CD4 lymphocyte and monocyte infiltration, neuronal apoptosis and neuronal loss were analyzed by immunohistochemistry.RESULTS:Patients who died in SH1 showed astrocyte activation, whereas those who died in SH2 also showed microglial activation, CD4 lymphocyte and monocyte infiltration, neuronal apoptosis and neuronal loss. These changes remained in patients in SH3, who also showed increased IL-1β and TNFα. Patients who died of liver cirrhosis did not show CD4 lymphocyte infiltration, neuronal apoptosis or increase in TNFα, but still showed glial activation, increased IL-1β and neuronal loss.CONCLUSIONS:Patients with steatohepatitis showed glial activation, immune cell infiltration, apoptosis and neuronal loss. Glial activation and neuronal loss remained in cirrhotic patients. This may explain the irreversibility of some cognitive alterations in hepatic encephalopathy. Cognitive reserve may contribute to different grades of cognitive impairment despite similar neuronal loss.

Multiple Myeloma (MM) is a plasma cell tumor, occurs more commonly in men than in women, differences in incidence by ethnic group have been reported, and exposure to different genotoxic agents has been described as risk factors. Epidemiological and genetic studies of MM in Latin America are scarce, so we created the Ibero-American Network for Multiple Myeloma Research (REDIMM), for the exchange and dissemination of information, standardization of protocols and genetic technologies. Eighteen countries were invited and after 5 years of work, REDIMM has 11 participating countries. Each country, with the exception of the United States whose representative explains the palliative care model, presents demographic, clinical laboratory, genetic, and type of treatment information. Each country manages the MM according to the conditions of the environment and the health system; however, the communication between the countries of the network allows the transfer of knowledge that is beneficial in the diagnosis and follow-up. The countries that make up the REDIMM would like to have more technology to make an early and accurate diagnosis of MM. However, the scenario of many Latin American countries is the lack of clinical laboratory tests and in some the total absence of genetics laboratories. In addition, the difficulties for diagnosis are added that it is usually late since patients move to large cities in advanced stages. The research shows that MM has a lower incidence than reported in North America and Europe, a low incidence of monoclonal gammopathy of uncertain significance in the region is described, younger patients than described in other populations are observed, and a relationship between exposure to genotoxics and the development of this cancer is evident. Non-hyperdiploid cases with a worse prognosis predominate, access to treatment is limited and survival time is shorter than reported in the United States and Europe. In Ecuadorian mestizo populations, differences in age and gender ratio are observed according to the predominant ancestry component studied by AIMs-INDELs. We conclude that characterizing the situation of the MM in Latin America will have an immediate and medium-term benefit for all participating institutions, and we hope in Latin America, which will have a favorable impact on myeloma patients.

The Covid-19 pandemic revealed a complex health problem for people and national health systems. Faced with the initial ignorance of the behavior of the SARS-COV-2 virus in populations, people turned to relief and alternative medicines. In Ecuador, the use of traditional or western medicine and the systematic approach of people to conventional medicine are evident realities. Our work aimed to assess the knowledge, attitudes and practices regarding Covid-19 and the use of formal and traditional medicine to treat the disease or contagion. An open, personal and confidential survey was carried out, with 158 questions on general data, ethnicity, health status, covid-19 tests, use of self-medication, use of medicinal plants or other chemical products, and use of antibiotics or antiparasitics, among other data. In the control of the patients, six months after finishing the survey, they were asked about the acceptance of the vaccine and the decision to be vaccinated or not. The results in 3,000 persons (50% female and 50% male) show frequent use of alternative or traditional medicine, even in health personnel or university studies. The study's conclusions reflect that people choose any of the therapies they have access to and even mix traditional treatments with traditional ones that are unproven or toxic. Keywords: knowledge, attitudes, practices, covid-19, formal medicine, traditional medicine

Background: Multiple myeloma (MM) is a clonal B cell malignancy characterized by the presence of multiple structural and numerical genetic alterations, including gains, losses and rearrangements of different chromosomal regions. Among them, the partial deletion of the long arm of chromosome 6 [del(6q)] is a common recurrent abnormality in MM, observed in 20-35% of patients. Despite this, there is no data about this alteration from MM patients in Latin America (LA). Aims: To evaluate frequency, distribution and clinical characteristics of MM patients with del(6q) in a multicenter study from the GELAMM (Grupo de Estudio Latinoamericano de MM). Methods: We retrospectively reviewed MM patients from Argentina, Chile, Ecuador and Uruguay, whose specimens were assessed by conventional cytogenetics and tested using interphase FISH between 2010 and 2020. Conventional cytogenetic analysis was performed on unstimulated bone marrow (BM) cells cultured. G-banded technique was used. FISH analysis was performed on unstimulated BM samples or on isolated plasma cells. The MM DNA probe panel was used. To compare clinical characteristics, a reference group of 105 MM patients without cytogenetic and FISH alterations (w/alt) (57 males; R-ISS: 1: 10.6%, 2: 50.3%, 3: 39.4%) was included. The study was approved by the local Ethics Committees of each Institution, in compliance with the Declaration of Helsinki. Results: A total of 220 patients with abnormal karyotypes were detected; 55 (25%) of them showed del(6q) (28 males; R-ISS: 1: 27.5%, 2: 31.1%, 3: 41.4%). Cytogenetic analysis showed simple karyotypes (SK; one or two alterations) in 51% of cases and complex karyotypes (CK; 3 or more alterations) in 49%. The distribution of modal number was: hypodiploid (33% of cases), hyperdiploid (30%), hypertriploid (11%), hyperhaploid (8%), pseudodiploid (7%), hypotriploid (7%) and hypotetraploid (4%). The most frequent breakpoints were 6q23 and 6q25 (32.7% each), followed by: 6q21 (29.1%), 6q13 (18.2%), 6q15 (16.4%) and 6q27 (10.9%). Most common alterations associated to del(6q) involved chromosomes: 1 (38.7% of cases), 13 (32.7%), 11 (30.9%), 3 (27.3%), 14, 15 and 19 (25.5% each). By FISH analysis, patients with CK showed high frequency of del(17p) (63.5%) and chromosome 1 alterations (61.5%). Translocations t(11;14) and t(4;14) were observed in 15% of cases each and t(14;16) in 10% of patients. Cases with del(6q) were older (61.4 years) than those w/alt (57.6 years) (p=0.0216). Analysis of clinical parameters showed increased lactate dehydrogenase and serum monoclonal M protein levels in patients with del(6q) than those w/alt (p<0.0001 and p=0.0353, respectively). Cases with CK also had higher creatinine levels (p=0.0276). Seventy percent of patients received proteasome inhibitor and immunomodulatory agents at induction. No differences in overall survival (OS) between patients with SK (82.2 months) compared to those w/alt (78.2 months) was seen, but a significant short OS in cases with del(6q) and CK (36.1 months) (p=0.003) was observed. Summary/Conclusion: To our knowledge, this is the first analysis of del(6q) in MM patients from LA. Our cohort had a similar frequency of del(6q) than published series, with particular involvement of 6q23 and 6q25 breakpoints. Interestingly, patients with del(6q) showed high frequency of chromosome 1 alterations, particularly in the context of CK, associated to poor clinical outcome. Our study reinforces the importance of conventional metaphase karyotyping, and its contribution to a better stratification and biologic characterization of MM patients.

Patients with non-alcoholic fatty liver disease (NAFLD) may show mild cognitive impairment. Neuroinflammation in the hippocampus mediates cognitive impairment in rat models of minimal hepatic encephalopathy (MHE). Treatment with rifaximin reverses cognitive impairment in a large proportion of cirrhotic patients with MHE. However, the underlying mechanisms remain unclear. The aims of this work were to assess if rats with mild liver damage, as a model of NAFLD, show neuroinflammation in the hippocampus and impaired cognitive function, if treatment with rifaximin reverses it, and to study the underlying mechanisms. Mild liver damage was induced with carbon-tetrachloride. Infiltration of immune cells, glial activation, and cytokine expression, as well as glutamate receptors expression in the hippocampus and cognitive function were assessed. We assessed the effects of daily treatment with rifaximin on the alterations showed by these rats. Rats with mild liver damage showed hippocampal neuroinflammation, reduced membrane expression of glutamate N-methyl-D-aspartate (NMDA) receptor subunits, and impaired spatial memory. Increased C-C Motif Chemokine Ligand 2 (CCL2), infiltration of monocytes, microglia activation, and increased tumor necrosis factor α (TNFα) were reversed by rifaximin, that normalized NMDA receptor expression and improved spatial memory. Thus, rifaximin reduces neuroinflammation and improves cognitive function in rats with mild liver damage, being a promising therapy for patients with NAFLD showing mild cognitive impairment.

The case of a 4-year-two-month-old female patient is presented, who consulted for a special phenotype: psychomotor retardation, short stature, microcephaly, large and low-set ears, small forehead, prominent brow ridges, labial commissure open, ocular hypertelorism, short neck, mammary hypertelorism and pectus excavatum. The objective of this study is to analyze a patient with unusual phenotypic traits, through physical examination, comparative analysis with other cases, and genetic studies. The cytogenetic study revealed a mosaic karyotype, mos 46,XX,r(15)(q26.3)/46,XX with the presence of the ring in 83%. The genetic mapping array study identified the loss of 3.5 Mb in 15q26.3. Among the genes lost in the terminal region of 15q, an interaction between their protein products was evidenced according to the STRING analysis. This is the second case of a ring chromosome 15 reported in Ecuador. And it would be the 101st in the world since 1966. The special phenotype of these individuals is related to the amount of genetic material lost. The genes involved in the formation of the ring, as well as the proteins that determine these genes and the relationships in different cellular pathways, are analyzed in silico in order to understand the pathophysiology of this disorder. Its diagnosis is mostly postnatal, so the clinical approach differs individually according to the symptoms and signs that appear.

The fundamental pillars of science are scientific research, technology and innovation (S+T+I). Without the development of each of these aspects, the results and scientific contributions of a country are limited. In Ecuador, the reality is very complex. Not only is the funding scarce, but it is not aligned with the current lines of research and researchers' specialty, accompanied by noncompliance with state policies and offers. In this environment, the participation of women could find limitations. Even so, we can verify that the level and impact of the publications between genres are balanced. We must strengthen science in Ecuador to place ourselves at the levels of other countries.

Se ha informado que la infección por SARS-CoV-2 tiene al menos tres aspectos: la capacidad patogénica del virus, la susceptibilidad y la interacción virus-huésped en un ambiente. Para varios virus, está demostrado que tienen receptores celulares específicos de unión con las células y son determinantes en la entrada o no del virus a las células. Para el virus SARS-CoV-2, se conoce que el receptor ACE2 (Enzima Convertidora de Angiotensina 2), es clave para que el virus se adhiera a la membrana celular del epitelio pulmonar, al neumocito. El receptor ACE2 tiene su gen específico con el mismo nombre localizado en el cromosoma Xp22.2 y tiene a su vez interacciones con algunos genes. Nos propusimos encontrar interacciones de proteínas que tengan relación con la entrada, sintomatología y progreso de la COVID-19 y con otras proteínas similares o coadyuvantes. Estas interacciones son extremadamente importantes para entender la fisiopatología de la enfermedad y los diversos grados de afectación que se han observado asintomáticos, leves, moderados, graves y críticos, lo que se conoce como heterogeneidad clínica. La heterogeneidad en los síntomas es probable que refleje una heterogeneidad de interacciones de proteínas que se encuentran interrelacionadas con la infección por el virus COVID-19 y su correlación entre sí. La meta final es encontrar los genes que comandan estas interacciones proteicas y asociarlas con la variación clínica. Este es un estudio inicial de interactoma proteico para continuar con el análisis de proteínas específicas y sus variantes en la población ecuatoriana.

COVID-19 was declared an international public health emergency in January, and a pandemic in March of 2020. There are over 125 million confirmed COVID-19 cases that have caused over 2.7 million deaths worldwide as of March 2021. COVID-19 is caused by the SARS-CoV-2 virus. SARS-CoV-2 presents a surface "spike" protein that binds to the ACE2 receptor to infect host cells. In addition to the respiratory tract, SARS-Cov-2 can also infect cells of the oral mucosa, which also express the ACE2 receptor. The spike and ACE2 proteins are highly glycosylated with sialic acid modifications that direct viral-host interactions and infection. Maackia amurensis seed lectin (MASL) has a strong affinity for sialic acid modified proteins and can be used as an antiviral agent. Here, we report that MASL targets the ACE2 receptor, decreases ACE2 expression and glycosylation, suppresses binding of the SARS-CoV-2 spike protein, and decreases expression of inflammatory mediators by oral epithelial cells that cause ARDS in COVID-19 patients. In addition, we report that MASL also inhibits SARS-CoV-2 infection of kidney epithelial cells in culture. This work identifies MASL as an agent with potential to inhibit SARS-CoV-2 infection and COVID-19 related inflammatory syndromes.

In patients with liver cirrhosis, minimal hepatic encephalopathy (MHE) is triggered by a shift in peripheral inflammation, promoting lymphocyte infiltration into the brain. Rifaximin improves neurological function in MHE by normalizing peripheral inflammation. Patients who died with steatohepatitis showed T-lymphocyte infiltration and neuroinflammation in the cerebellum, suggesting that MHE may already occur in these patients. The aims of this work were to assess, in a rat model of mild liver damage similar to steatohepatitis, whether: (1) the rats show impaired motor coordination in the early phases of liver damage; (2) this is associated with changes in the immune system and infiltration of immune cells into the brain; and (3) rifaximin improves motor incoordination, associated with improved peripheral inflammation, reduced infiltration of immune cells and neuroinflammation in the cerebellum, and restoration of the alterations in neurotransmission. Liver damage was induced by carbon tetrachloride (CCl4) injection over four weeks. Peripheral inflammation, immune cell infiltration, neuroinflammation, and neurotransmission in the cerebellum and motor coordination were assessed. Mild liver damage induces neuroinflammation and altered neurotransmission in the cerebellum and motor incoordination. These alterations are associated with increased TNFa, CCL20, and CX3CL1 in plasma and cerebellum, IL-17 and IL-15 in plasma, and CCL2 in cerebellum. This promotes T-lymphocyte and macrophage infiltration in the cerebellum. Early treatment with rifaximin prevents the shift in peripheral inflammation, immune cell infiltration, neuroinflammation, and motor incoordination. This report provides new clues regarding the mechanisms of the beneficial effects of rifaximin, suggesting that early rifaximin treatment could prevent neurological impairment in patients with steatohepatitis.

Recent advances in adeno-associated viral (AAV) capsid variants with novel oligotropism require validation in models of disease in order to be viable candidates for white matter disease gene therapy. We present here an assessment of the biodistribution, tropism, and efficacy of a novel AAV capsid variant (AAV/ Olig001) in a model of Canavan disease. We first define a combination of dose and route of administration of an AAV/Olig001-GFP reporter conducive to widespread CNS oligodendrocyte transduction in acutely symptomatic animals that model the Canavan brain at time of diagnosis. Administration of AAV/Olig001-GFP resulted in >70% oligotropism in all regions of interest except the cerebellum without the need for lineage-specific expression elements. Intracerebroventricular infusion into the cerebrospinal fluid (CSF) was identified as the most appropriate route of administration and employed for delivery of an AAV/Olig001 vector to reconstitute oligodendroglial aspartoacylase (ASPA) in adult Canavan mice, which resulted in a dose-dependent rescue of ASPA activity, motor function, and a near-total reduction in vacuolation. A head-to-head efficacy comparison with astrogliotropic AAV9 highlighted a significant advantage conferred by oligotropic AAV/Olig001 that was independent of overall transduction efficiency. These results support the continued development of AAV/Olig001 for advancement to clinical application to white matter disease.

•The social deficit in ASD are attributed to dysfunction mirror neuron networks concentrated in the inferior parietal lobule (IPL). •We recruited 4 children with ASD and implemented high frequency rTMS targeting the left-IPL. •The outcome measures included ADOS-2, EVT-2, SRS-2, and D-KEFS. The last 2 measures showed trend-level improvement. •No adverse event noted.

Telomere maintenance mechanisms (TMM) are used by cancer cells to avoid apoptosis, 85–90% reactivate telomerase, while 10–15% use the alternative lengthening of telomeres (ALT). Due to anti-telomerase-based treatments, some tumors switch from a telomerase-dependent mechanism to ALT; in fact, the co-existence between both mechanisms has been observed in some cancers. Although different elements in the ALT pathway are uncovered, some molecular mechanisms are still poorly understood. Therefore, with the aim to identify potential molecular markers for the study of ALT, we combined in silico approaches in a 411 telomere maintenance gene set. As a consequence, we conducted a genomic analysis of these genes in 31 Pan-Cancer Atlas studies from The Cancer Genome Atlas and found 325,936 genomic alterations; from which, we identified 20 genes highly mutated in the cancer studies. Finally, we made a protein-protein interaction network and enrichment analysis to observe the main pathways of these genes and discuss their role in ALT-related processes, like homologous recombination and homology directed repair. Overall, due to the lack of understanding of the molecular mechanisms of ALT cancers, we proposed a group of genes, which after ex vivo validations, could represent new potential therapeutic markers in the study of ALT.