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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.

Background Congenital insensitivity to pain with anhidrosis (CIPA) is an extremely rare autosomal recessive disorder characterized by insensitivity to pain, inability to sweat and intellectual disability. CIPA is caused by mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1) that encodes the high-affinity receptor of nerve growth factor (NGF). Case presentation Here, we present clinical and molecular findings in a 9-year-old girl with CIPA. The high-altitude indigenous Ecuadorian patient presented several health problems such as anhidrosis, bone fractures, self-mutilation, osteochondroma, intellectual disability and Riga-Fede disease. After the mutational analysis of NTRK1, the patient showed a clearly autosomal recessive inheritance pattern with the pathogenic mutation rs763758904 (Arg602*) and the second missense mutation rs80356677 (Asp674Tyr). Additionally, the genomic analysis showed 69 pathogenic and/or likely pathogenic variants in 46 genes possibly related to phenotypic heterogeneity, including the rs324420 variant in the FAAH gene. The gene ontology enrichment analysis showed 28 mutated genes involved in several biological processes. As a novel contribution, the protein-protein interaction network analysis showed that NTRK1, SPTBN2 and GRM6 interact with several proteins of the pain matrix involved in the response to stimulus and nervous system development. Conclusions This is the first study that associates clinical, genomics and networking analyses in a Native American patient with consanguinity background in order to better understand CIPA pathogenesis.

Telomere maintenance mechanisms (TMM) are used by cancer cells to avoid apoptosis, 85&ndash, 90% reactivate telomerase, while 10&ndash, 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.

Background Since 1969, 49 cases have been presented on ring chromosome 4. All of these cases have been characterized for the loss of genetic material. The genes located in these chromosomal regions are related to the phenotype. Case presentation A 10-year-old Ecuadorian Mestizo girl with ring chromosome 4 was clinically, cytogenetically and molecularly analysed. Clinical examination revealed congenital anomalies, including microcephaly, prominent nose, micrognathia, low set ears, bilateral clinodactyly of the fifth finger, small sacrococcygeal dimple, short stature and mental retardation. Cytogenetic studies showed a mosaic karyotype, mos 46,XX,r(4)(p16.3q35.2)/46,XX, with a ring chromosome 4 from 75 to 79% in three studies conducted over ten years. These results were confirmed by fluorescence in situ hybridization (FISH). Loss of 1.7 Mb and gain of 342 kb in 4p16.3 and loss of 3 Mb in 4q35.2 were identified by high-resolution mapping array. Conclusion Most cases with ring chromosome 4 have deletion of genetic material in terminal regions; however, our case has inv dup del rearrangement in the ring chromosome formation. Heterogeneous clinical features in all cases reviewed are related to the amount of genetic material lost or gained. The application of several techniques can increase our knowledge of ring chromosome 4 and its deviations from typical “ring syndrome.”

Trisomy 9p syndrome is the fourth most frequent chromosome aberration seen in infants. Duplication of the critical region 9p22p24 leads to mental retardation, psychomotor delay, and craniofacial and digital anomalies. We report a 2-year-old Ecuadorian girl with Trisomy 9p syndrome. Although her phenotype shares characteristics of Noonan syndrome, Giemsa trypsin banding technique shows there is an extra chromosomal segment on chromosome 14, and array analysis shows that it belongs to a duplication of 38 Mb of 9p13.1p24.3. Fluorescence in situ hybridization analysis detected three signals from 9p chromosome. The duplication is de novo, being another unique case of the few reported in the literature.

Colorectal cancer (CRC) is a major health problem with an estimated 1. 8 million new cases worldwide. To date, most CRC studies have focused on DNA-related aberrations, leaving post-transcriptional processes under-studied. However, post-transcriptional alterations have been shown to play a significant part in the maintenance of cancer features. RNA binding proteins (RBPs) are uprising as critical regulators of every cancer hallmark, yet little is known regarding the underlying mechanisms and key downstream oncogenic targets. Currently, more than a thousand RBPs have been discovered in humans and only a few have been implicated in the carcinogenic process and even much less in CRC. Identification of cancer-related RBPs is of great interest to better understand CRC biology and potentially unveil new targets for cancer therapy and prognostic biomarkers. In this work, we reviewed all RBPs which have a role in CRC, including their control by microRNAs, xenograft studies and their clinical implications.

The history of Ecuador was marked by the arrival of Europeans with Africans, resulting in the mixture of Native Americans with Africans and Europeans. The present study contributes to the knowledge of the Ecuadorian mestizo population by offering information about ancestry and ethnic heterogeneity. Forty-six AIM-InDels (Ancestry Informative Insertion/Deletion Markers) were used to obtain information on 240 Ecuadorian individuals from three regions (Amazonia, the Highlands, and the Coast). As a result, the population involved a significant contribution from Native Americans (values up to 51%), followed by Europeans (values up to 33%) and Africans (values up to 13%). Furthermore, we compared the data obtained with nine previously reported scientific articles on autosomal, mitochondrial DNA and Y chromosomes. The admixture results correspond to Ecuador’s historical background and vary slightly between regions.

Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide. Over the last decades, several studies have shown that tumor-related genomic alterations predict tumor prognosis, drug response and toxicity. These observations have led to the development of a number of precision therapies based on individual genomic profiles. As part of these approaches, pharmacogenomics analyses genomic alterations that may predict an efficient therapeutic response. Studying these mutations as biomarkers for predicting drug response is of a great interest to improve precision medicine. Here we conduct a comprehensive review of the main pharmacogenomics biomarkers and genomic alterations affecting enzyme activity, transporter capacity, channels and receptors, and therefore the new advances in CRC precision medicine to select the best therapeutic strategy in populations worldwide, with a focus on Latin America.

Congenital insensitivity to pain with anhidrosis (CIPA) is an extremely rare autosomal recessive disorder characterized by insensitivity to pain, inability to sweat and intellectual disability. CIPA is caused by mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1) that encodes the high-affinity receptor of nerve growth factor (NGF). Patients with CIPA lack the primary afferents and sympathetic postganglionic neurons leading to lack of pain sensation and the presence of anhidrosis, respectively. Herein, we conducted a genomic analysis of 4,811 genes and 18,933 variants, including 54 mutations of NTRK1 in a high-altitude indigenous Ecuadorian patient with CIPA. As results, the patient presented 87.8% of Native American ancestry, 6.6% of African ancestry and 5.6% of European ancestry. The mutational analysis of the kinase domain of NTRK1 showed two pathogenic mutations, rs80356677 (Asp674Tyr) and rs763758904 (Arg602*). The genomic analysis showed 68 pathogenic and/or likely pathogenic variants in 45 genes, and two variants of uncertain significance in CACNA2D1 (rs370103843) and TRPC4 (rs80164537) genes involved in the pain matrix. The GO enrichment analysis showed 28 genes with relevant mutations involved in several biological processes, cellular components and molecular functions. In addition, the protein-protein interaction (PPi) networking analysis showed that NTRK1, SPTBN2 and GRM6 interact with several proteins of the pain matrix. In conclusion, this is the first time that a study associates genomic, ancestral and networking data in a high-altitude Native American Ecuadorian patient with consanguinity background in order to better understand CIPA pathogenesis.

Background. Many studies, comparing the health associated risks of electronic cigarettes with conventional cigarettes focus mainly on the common chemical compounds found between them. Aim. Review chemical compounds found exclusively in electronic cigarettes and describe their toxic effects, focusing on electronic-cigarette-only and dual electronic-cigarette and conventional cigarette users. Data Sources. Literature search was carried out using PubMed. Study Eligibility Criteria. Articles related exclusively to conventional and electronic cigarettes’ chemical composition. Articles which reported to be financed from tobacco or electronic cigarettes industries, not reporting source of funding, not related to the chemical composition of electronic and conventional cigarettes and not relevant to tobacco research were excluded. Methods and Results. Chemical compounds reported in the selected studies were tabulated using the Chemical Abstracts Service registry number for chemical substances information. A total of 50 chemical compounds were exclusively reported to be present in electronic cigarettes. Crucial health risks identified were: eye, skin, and respiratory tract irritation, with almost 50% of incidence, an increment of 10% in cytotoxic effects, when compared to compounds in common with conventional cigarettes and around 11% of compounds with unknown effects to human health. Limitations. Articles reporting conflicts of interest. Conclusions and Implications of Key Findings. Despite being considered as less harmful for human health, compounds found in electronic cigarettes are still a matter of research and their effects on health are yet unknown. The use of these devices is not recommended for first time users and it is considered hazardous for dual users.

Ecuador is located between latitudes 2°N and 5°S and limits the Pacific Ocean on the west, Colombia on the north, and Peru on the south and east (Fig. 1). Its capital, Quito, stands at 2850 m (9350 ft.) above sea level. The country has four different geographic regions, the Coast (west of the Andes), the Sierra (Interandean highlands), the Amazon (east of the Andes), and the Insular region (Galapagos Islands). It is also divided into 24 provinces; six in the Coast, 11 in the Sierra, six in the Amazon, and one in the Insular region. Figure 1 Political map of Ecuador. Ecuador's surface area is 256,369 km2 (98,985 sq miles). The population in the last National Census in 2010 was 14,483,499 and it is estimated to be above 15 million as of 2015 (National Institute of Census and Statistics, INEC, www.inec.gob.ec). Life expectancy in Ecuador is 75.6 years (CIA, World Fact Book). Its gross domestic product (GDP) per capita was $5932 with a GDP growth rate of 4.05% in 2013 (Ecuadorian Ministry of Finances).

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer with the highest incidence worldwide. HNSCC is often diagnosed at advanced stages, incurring significant high mortality and morbidity. The use of saliva, as a noninvasive tool for the diagnosis of cancer, has recently increased. Salivary microRNAs (miRNAs) have emerged as a promising molecular tool for early diagnosis of HNSCC. The aim was to identify the differential expression of salivary miRNAs associated with HNSCC in the high altitude mestizo Ecuadorian population. Using PCR Arrays, miR-122-5p, miR-92a-3p, miR-124-3p, miR-205-5p, and miR-146a-5p were found as the most representative ones. Subsequently, miRNAs expression was confirmed in saliva samples from 108 cases and 108 controls. miR-122-5p, miR-92a-3p, miR-124-3p, and miR-146a-5p showed significant statistical difference between cases and controls with areas under the curve (AUC) of 0.73 (p < 0.001), 0.70 (p < 0.001), 0.71 (p = 0.002), and 0.66 (p = 0.008), respectively. miRNAs were also deregulated in between HNSCC localizations. A differentiated expression of miR-122-5p between oral cancer and oropharynx cancer (AUC of 0.96 p = 0.01) was found: miR-124-3p between larynx and pharynx (AUC = 0.97, p < 0.01) and miR-146a-5p between larynx, oropharynx, and oral cavity (AUC = 0.96, p = 0.01). Moreover, miR-122-5p, miR-124-3p, miR-205-5p, and miR-146a-5p could differentiate between HPV+ and HPV- (p=0.004). Finally, the expression profiles of the five miRNAs were evaluated to discriminate HNSCC patient’s tumor stages (TNM 2-4). miR-122-5p differentiates TNM 2 and 3 (p = 0.002, AUC = 0.92), miR-124-3p TNM 2, 3, and 4 (p < 0.001, AUC = 98), miR-146a-5p TNM 2 and 3 (p < 0.001, AUC = 0.97), and miR-92a-3p TNM 3 (p < 0.001, AUC = 0.99). Taken together, these findings show that altered expression of miRNAs could be used as biomarkers for HNSCC diagnosis in the high altitude mestizo Ecuadorian population.

Breast cancer is the leading cause of cancer-related death among women worldwide. AKT1 encodes the kinase B alpha protein. The rs121434592, rs12881616, rs11555432, rs11555431, rs2494732, and rs3803304 single nucleotide polymorphisms have been identified in the AKT1 kinase gene. Activated AKT1 phosphorylates downstream substrates regulating cell growth, metabolism, apoptosis, angiogenesis, and drug responses. It is essential to know how breast cancer risk is associated with histopathological and immunohistochemical characteristics and genotype polymorphisms in a high altitude Ecuadorian mestizo population. This is a retrospective case-control study. DNA was extracted from 185 healthy and 91 affected women who live 2,800 meters above sea level. Genotypes were determined by genomic sequencing. We found a possible association between the noncoding intronic variant rs3803304 and breast cancer risk development: GG (odds ratio [OR] = 5.2; 95% confidence interval [CI] = 1.3-20.9; P ≤ 0.05; Q > 0.05). Regarding pathologic characteristics, we found significant risk between estrogen receptor, progesterone receptor, and HER2 status and molecular subtypes (P ≤ 0.001; Q ≤ 0.05). On the other hand, we did not find risk between variants and histopathological characteristics. Despite the small sample size, we found that the intronic variant, AKT1 rs3803304, may act as a predictive biomarker in the risk of developing breast cancer in the high altitude Ecuadorian mestizo population.

Prostate cancer (PC) is the second most commonly diagnosed type of cancer in males with 1,114,072 new cases in 2015. The MTHFR enzyme acts in the folate metabolism, which is essential in methylation and synthesis of nucleic acids. MTHFR C677T alters homocysteine levels and folate assimilation associated with DNA damage. Androgens play essential roles in prostate growth. The SRD5A2 enzyme metabolizes testosterone and the V89L polymorphism reduces in vivo SRD5A2 activity. The androgen receptor gene codes for a three-domain protein that contains two polymorphic trinucleotide repeats (CAG, GGC). Therefore, it is essential to know how PC risk is associated with clinical features and polymorphisms in high altitude Ecuadorian mestizo populations. We analyzed 480 healthy and 326 affected men from our three retrospective case-control studies. We found significant association between MTHFR C/T (odds ratio [OR] = 2.2;P=0.009), MTHFR C/T+T/T (OR = 2.22;P=0.009), and PC. The SRD5A2 A49T substitution was associated with higher pTNM stage (OR = 2.88;P=0.039) and elevated Gleason grade (OR = 3.15;P=0.004). Additionally, patients with ≤21 CAG repeats have an increased risk of developing PC (OR = 2.99;P<0.001). In conclusion, genotype polymorphism studies are important to characterize genetic variations in high altitude mestizo populations.

Purpose: Myeloma is a clonal malignancy of plasma cells. Poor-prognosis risk is currently identified by clinical and cytogenetic features. However, these indicators do not capture all prognostic information. Gene expression analysis can be used to identify poor-prognosis patients and this can be improved by combination with information about DNA-level changes. Experimental Design: Using single nucleotide polymorphism–based gene mapping in combination with global gene expression analysis, we have identified homozygous deletions in genes and networks that are relevant to myeloma pathogenesis and outcome. Results: We identified 170 genes with homozygous deletions and corresponding loss of expression. Deletion within the “cell death” network was overrepresented and cases with these deletions had impaired overall survival. From further analysis of these events, we have generated an expression-based signature associated with shorter survival in 258 patients and confirmed this signature in data from two independent groups totaling 800 patients. We defined a gene expression signature of 97 cell death genes that reflects prognosis and confirmed this in two independent data sets. Conclusions: We developed a simple 6-gene expression signature from the 97-gene signature that can be used to identify poor-prognosis myeloma in the clinical environment. This signature could form the basis of future trials aimed at improving the outcome of poor-prognosis myeloma. Clin Cancer Res; 16(6); 1856–64

A total of 108 individuals from the Ecuadorian population from rural and urban places were analyzed for twoCYP1A1gene polymorphisms. The frequency of the val allele at codon 462 was 0.50, while the frequency of the Msp I restriction site, m2 allele at the T6235C position was 0.70. These polymorphisms in Ecuador have higher frequencies if we compare with others around the world, with the exception of some South American population in Brazil and Chile.

Background The use of human embryonic stem cells (hESCs) in research is increasing and hESCs hold the promise for many biological, clinical and toxicological studies. Human ESCs are expected to be chromosomally stable since karyotypic changes represent a pitfall for potential future applications. Recently, several studies have analysed the genomic stability of several hESC lines maintained after prolonged in vitro culture but controversial data has been reported. Here, we prompted to compare the chromosomal stability of three hESC lines maintained in the same laboratory using identical culture conditions and passaging methods. Results Molecular cytogenetic analyses performed in three different hESC lines maintained in parallel in identical culture conditions revealed significant differences among them in regard to their chromosomal integrity. In feeders, the HS181, SHEF-1 and SHEF-3 hESC lines were chromosomally stable up to 185 passages using either mechanical or enzymatic dissection methods. Despite the three hESC lines were maintained under identical conditions, each hESC line behaved differently upon being transferred to a feeder-free culture system. The two younger hESC lines, HS181 (71 passages) and SHEF-3 (51 passages) became chromosomally unstable shortly after being cultured in feeder-free conditions. The HS181 line gained a chromosome 12 by passage 17 and a marker by passage 21, characterized as a gain of chromosome 20 by SKY. Importantly, the mosaicism for trisomy 12 gradually increased up to 89% by passage 30, suggesting that this karyotypic abnormality provides a selective advantage. Similarly, the SHEF-3 line also acquired a trisomy of chromosome 14 as early as passage 10. However, this karyotypic aberration did not confer selective advantage to the genetically abnormal cells within the bulk culture and the level of mosaicism for the trisomy 14 remained overtime between 15%–36%. Strikingly, however, a much older hESC line, SHEF-1, which was maintained for 185 passages in feeders did not undergo any numerical or structural chromosomal change after 30 passages in feeder-free culture and over 215 passages in total. Conclusion These results support the concept that feeder-free conditions may partially contribute to hESC chromosomal changes but also confirm the hypothesis that regardless of the culture conditions, culture duration or splitting methods, some hESC lines are inherently more prone than others to karyotypic instability.