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Background: In Peru, 32,970 people were diagnosed with tuberculosis (TB) in 2019. Although TB treatment is effective, 3.4%–13% is associated with significant adverse drug reactions (ADR), considering drug-induced liver injury (DILI) as the most prevalent. Among the first-line anti-TB drugs, isoniazid (INH) is primarily responsible for the occurrence of DILI. INH is metabolized in the liver by the enzymes N-acetyltransferase-2 (NAT2) and Cytochrome P450 2E1 (CYP2E1). Based on the previous studies, we hypothesized that the interactions between slow CYP2E1 genotype and NAT2 slow acetylators will induce DILI in TB patients. Methods: In this cross-sectional study, all 377 participants completed their anti-TB treatment, and we genotyped SNPs: rs1041983, rs1801280, rs1799929, rs1799930, rs1208, and rs1799931 for NAT2 and rs3813867 and rs2031920 for CYP2E1. Results: We found that rapid, intermediate, and slow NAT2 acetylator were 15%, 38%, and 47%, respectively, in the general population. Intermediate NAT2 acetylator is the least prevalent among patients with adverse reactions (p = 0.024). We did not confirm our hypothesis, however, we found that the combination of intermediate NAT2 acetylators and CYP2E1 c1/c1 genotype significantly protected (OR = 0.16; p = 0.049) against the development of DILI in our population. Conclusion: We propose that the presence of NAT2 intermediate and CYP2E1 c1/c1 genotype could help in therapeutic drug monitoring, and optimize its therapeutic benefits while minimizing its risk for side effects or toxicity.

Background We determined the frequency of genetic polymorphisms in three anti‐TB drug metabolic proteins previously reported: N‐acetyltransferase 2 (NAT2), cytochrome P450 2E1 (CYP2E1), and arylacetamide deacetylase (AADAC) within a Peruvian population in a cohort of TB patients. Methods We genotyped SNPs rs1041983, rs1801280, rs1799929, rs1799930, rs1208, and rs1799931 for NAT2; rs3813867 and rs2031920 for CYP2E1; and rs1803155 for AADAC in 395 participants completed their antituberculosis treatment. Results Seventy‐four percent of the participants are carriers of slow metabolizer genotypes: NAT2*5, NAT2*6, and NAT2*7, which increase the sensitivity of INH at low doses and increase the risk of drug‐induced liver injuries. Sixty‐four percent are homozygous for the wild‐type CYP2E1*1A allele, which could increase the risk of hepatotoxicity. However, 16% had a NAT2 fast metabolizer phenotype which could increase the risk of acquiring resistance to INH, thereby increasing the risk of multidrug‐resistant (MDR) or treatment failure. The frequency of rs1803155 (AADAC*2 allele) was higher (99.9%) in Peruvians than in European American, African American, Japanese, and Korean populations. Conclusions This high prevalence of slow metabolizers for isoniazid in the Peruvian population should be further studied and considered to help individualize drug regimens, especially in countries with a great genetic diversity like Peru. These data will help the Peruvian National Tuberculosis Control Program develop new strategies for therapies., High prevalence of slow metabolizers for isoniazid in the Peruvian population should be further studied and considered to help individualize drug regimens, especially in countries with a great genetic diversity like Peru.

Peru is a pluricultural and ethnically diverse country located in middle west of South America. It is the fourth largest country (1,285,216 km2) in area in South America, bordered in the north by Ecuador and Colombia, in the south by Chile, south east by Bolivia, by Brazil in the east and by the Pacific Ocean in the west. Peru has one of the most diverse climates, geographical and ecological in the world, from tropical or subtropical dessert to glacial in highland mountains to Amazon jungle. Peru is divided into 24 geopolitical regions with a central government. According to last national census in 2017, Peruvian populations accounts for 31,237,385 inhabitants (Instituto Nacional de Estadistica e Informatica [INEI], 2017). Most of Peru's population lives in the Coastal area, with almost one third of the nation's population living in Lima, the largest city with approximately 11 million people. Rural and urban population has changed over the last 50 years due to migration waves in the 1950s from rural to urban sites mainly located in the coast causing decrease or disappearance of native communities. Revisado por pares

Western South America was one of the worldwide cradles of civilization. The well known Inca Empire was the tip of the iceberg of a cultural and biological evolutionary process that started 14-11 thousand years ago. Genetic data from 18 Peruvian populations reveal that: (1) The between-population homogenization of the central-southern Andes and its differentiation with respect to Amazonian populations of similar latitudes do not extend northward. Instead, longitudinal gene flow between the northern coast of Peru, Andes and Amazonia accompanied cultural and socioeconomic interactions revealed by archeological studies. This pattern recapitulates the environmental and cultural differentiation between the fertile north, where altitudes are lower; and the arid south, where the Andes are higher, acting as a genetic barrier between the sharply different environments of the Andes and Amazonia (2). The genetic homogenization between the populations of the arid Andes is not only due to migration during the Inca Empire or the subsequent colonial period. It started at least during the earlier expansion of the pre-Inca Wari Empire (600-1000 YBP) (3) This demographic history allowed for cases of positive natural selection in the high and arid Andes vs. the low Amazon tropical forest: in the Andes, HAND2-AS1 (heart and neural crest derivatives expressed 2 antisense RNA1, related with cardiovascular function) and DUOX2 (dual oxidase 2, related to thyroid function and innate immunity) genes; in the Amazon, the gene encoding for the CD45 protein, essential for antigen recognition by T/B lymphocytes in viral-host interaction, consistent with the host-virus arms race hypothesis.

SUMMARYGuillain-Barre Syndrome (GBS) is considered a complex disorder with significant environmental effect and genetic susceptibility. Genetic polymorphisms in CD1E, CD1A, IL-17 and/or ICAM-1 genes had been proposed as susceptibility genetic variants for GBS mainly in Caucasian population. This study explores the association between selected polymorphisms in these genes and GBS susceptibility in confirmed GBS cases reported in mestizo population from northern Peru during the most recent GBS outbreak of May 2018. A total of 9 non-related cases and 11 controls were sequenced for the polymorphic regions of CD1A, CD1E, IL-17 and ICAM-1 genes. We found a significant protective association between heterozygous GA genotype in ICAM-1 gene (241Gly / Arg) and GBS (p IL-17 was monomorphic in both controls and patients. No significant differences were found in the frequency of SNPs in CD1A and CD1E between the group with GBS patients and healthy controls. Further studies with larger sample size will be required to validate these findings.

Significance Through the Peruvian Genome Project we generate and analyze the genomes of 280 individuals where the majority have >90% Native American ancestry and explore questions at the interface of evolutionary genetics, history, anthropology, and medicine. This is the most extensive sampling of high-coverage Native American and mestizo whole genomes to date. We estimate an initial peopling of Peru was rapid and began by 12,000 y ago. In addition, the mestizo populations exhibit admixture between Native American groups prior to their Spanish admixture and was likely influenced by the Inca Empire and Spanish conquest. Our results address important Native American population history questions and establish a dataset beneficial to address the underrepresentation of Native American ancestry in sequencing studies., Native Americans from the Amazon, Andes, and coastal geographic regions of South America have a rich cultural heritage but are genetically understudied, therefore leading to gaps in our knowledge of their genomic architecture and demographic history. In this study, we sequence 150 genomes to high coverage combined with an additional 130 genotype array samples from Native American and mestizo populations in Peru. The majority of our samples possess greater than 90% Native American ancestry, which makes this the most extensive Native American sequencing project to date. Demographic modeling reveals that the peopling of Peru began ∼12,000 y ago, consistent with the hypothesis of the rapid peopling of the Americas and Peruvian archeological data. We find that the Native American populations possess distinct ancestral divisions, whereas the mestizo groups were admixtures of multiple Native American communities that occurred before and during the Inca Empire and Spanish rule. In addition, the mestizo communities also show Spanish introgression largely following Peruvian Independence, nearly 300 y after Spain conquered Peru. Further, we estimate migration events between Peruvian populations from all three geographic regions with the majority of between-region migration moving from the high Andes to the low-altitude Amazon and coast. As such, we present a detailed model of the evolutionary dynamics which impacted the genomes of modern-day Peruvians and a Native American ancestry dataset that will serve as a beneficial resource to addressing the underrepresentation of Native American ancestry in sequencing studies.

Tuberculosis is a health problem worldwide with one-third of the population infected with the Mycobacterium tuberculosis bacilli. The first-line of treatment for tuberculosis includes the drugs Isoniazid (INH) and Rifampicin (RIF) metabolized in the liver. Drug metabolism is directly related to the genetic variation of NAT2 and CYP2E1 (associated with INH metabolism) and AADAC (associated with RIF metabolism), and the effects produced in an individual may be a fast, intermediate or slow metobolizer. Polymorphisms in genes of people in standard tuberculosis treatment can cause effects on drug metabolism with consequences of hepatotoxicity and even drug resistance. Countries have began clinical trials focusedon personalization of tuberculosis treatment to reduce the consequences for patients in treatment. In countries like Peru, where high rates of tuberculosis are recorded and therefore more people in treatment, the pharmacogenomic of individuals becomes a crucial tool for an optimum tuberculosis treatment. This review highlights the importance of having pharmacogenomic studies and having the identification of polymorphisms associated to the metabolism of theanti-tuberculosis drugs in our Peruvian population. La tuberculosis es un problema de salud Pública a nivel mundial con un tercio de la población infectada por el bacilo Mycobacterium tuberculosis. El tratamiento de primera línea incluye a las drogas isoniazida (INH) y rifampicina (RIF) metabolizadas en el hígado. La metabolización de drogas está directamente relacionada con la variación genética de NAT2 y CYP2E1 (asociados a metabolismo de INH) y AADAC (asociados a metabolismo de RIF), y los efectos pueden producir que un individuo sea metabolizador rápido, intermedio o lento. Los polimorfismos en genes de personas con tratamiento estándar de tuberculosis pueden ocasionar efectos en el metabolismo de drogas con consecuencias de hepatoxicidad e, incluso, posible drogorresistencia. Algunos países han empezado ensayos clínicos enfocados en la personalización del tratamiento a tuberculosis para reducir las consecuencias en pacientes en tratamiento. En países como el Perú, donde se registran altos índices de tuberculosis y, por consiguiente, más población en tratamiento, la farmacogenómica de individuos se convierte en una herramienta crucial para un óptimo tratamiento. La presente revisión destaca la importancia de tener estudios en farmacogenómica e identificar los polimorfismos asociados al metabolismo de las drogas antituberculosas en nuestra población peruana.

Background The emergence of multidrug-resistant strains is a major health problem especially for countries with high TB incidence such as Peru. In this study, we evaluated High Resolution Melting (HRM) assay in Peruvian isolates for the detection of mutations within rpoB, katG genes and promoter region inhA to determine isoniazid and rifampicin resistance in Mycobacterium tuberculosis (Mtb). Methods DNA samples extracted from a total of 167 clinical isolates of Mtb, 89 drug-sensitive and 78 multidrug-resistant, were blindly analyzed by HRM analysis and verified by DNA sequencing. Results The HRM analysis generated patterns that were specific to distinguish between sensitive and resistance isolates. The sensitivity and specificity of the HRM assays in comparison with drug susceptibility testing (DST) for detection of rifampicin resistance were 98.7 % and 97.5 %, and for isoniazid resistance were 98.7 % and 100 %. Conclusion This study suggests that HRM Analysis could help with rapid diagnosis of MDR-TB cases in Peru.

The most common therapeutic strategy for the treatment of cancer uses antimetabolites, which block uncontrolled division of cancer cells and kill them. However, such antimetabolites also kill normal cells, thus yielding detrimental side effects. This emphasizes the need for an alternative therapy, which would have little or no side effects. Our approach involves designing genetic means to alter surface lipid determinants that induce phagocytosis of cancer cells. The specific target of this strategy has been the enzyme activity termed aminophospholipid translocase (APLT) or flippase that causes translocation of phosphatidylserine (PS) from the outer to the inner leaflet of the plasma membrane in viable cells. Efforts to identify the enigmatic, plasma membrane APLT of mammalian cells have led investigators to some P-type ATPases, which have often proven to be the APLT of internal membranes rather than the plasma membrane. By measuring kinetic parameters for the plasma membrane APLT activity, we have shown that the P-type ATPase Atp8a1 is the plasma membrane APLT of the tumorigenic N18 cells, but not the non-tumorigenic HN2 (hippocampal neuron x N18) cells. Targeted knockdown of this enzyme causes PS externalization in the N18 cells, which would trigger phagocytic removal of these cells. But how would we specifically express the mutants or antisense Atp8a1 in the cancer cells? This has brought us to a glycosyltransferase, GnT-V, which is highly expressed in the transformed cells. By using the GnT-V promoter to drive a luciferase reporter gene we have demonstrated a dramatic increase in luciferase expression selectively in tumor cells. The described strategy could be tested for the removal of cancer cells without the use of antimetabolites that often kill normal cells.

Objective Treatment options are limited for patients with uterine serous carcinoma (USC). Knowledge of USC's somatic mutation landscape is rapidly increasing, but its role in hereditary cancers remains unclear. We aim to evaluate the frequency and characteristics of germline mutations in genes commonly implicated in carcinogenesis, including those within homologous recombination (HR) and mismatch repair (MMR) pathways in patients with pure USC. Methods By using targeted capture exome sequencing, 43 genes were analyzed in a cohort of 7 consecutive patients with paired tumor and non-tumor USC samples in our institutional tumor repository. Mutations predicted to have damaging effects on protein function are validated by Sanger Sequencing. Results We found 21 germline mutations in 11 genes in our USC cohort. Five patients harbored 7 germline mutations (33.3%) within genes involved in the HR pathway, RAD51D being the most common. Four patients had 9 (42.8%) germline mutations in hereditary colon cancer genes, most commonly MLH. All patients (42.7%) who are platinum-sensitive had HR germline mutations (RAD50, NBN, ATM). Patients with HER2 overexpression (2/7, 28.6%) had germline HR mutations and were platinum-sensitive. Three patients in our cohort reported a personal history of breast cancer, one with HR germline mutation, and 2 in patients with germline mutations in HCC genes. In addition, 5 out of 7 patients had germline mutations in genes associated with growth factor signaling pathway. Conclusions A significant proportion of our cohort harbor germline mutations in DNA repair genes. This may be associated with the high rate of breast cancer in our patients and their family, and suggests a targeted cohort for genetic counseling. If validated in a larger cohort, our findings may allow clinicians to expand therapeutic options to include targeted therapies and inclusion of USC patient in preventative and genetic counseling.

Amphiregulin, like other ErbB ligands, is synthesized as a pro-protein which requires cleavage at the cell surface to release the active signaling domain. Prior studies using a variety of approaches have not yielded a consensus about the precise cleavage site. Here we report the purification and protein sequencing of the cell-associated human Amphiregulin stalk which remains following cleavage of the signaling domain. These data indicate that human Amphiregulin is cleaved at Lysine 187, a site homologous to the cleavage site reported in the mouse protein and distinct from the Lysine 184 site previously reported for the human protein.

Infiltration of the tumor microenvironment by macrophages is associated with poor outcomes in breast cancer and other solid tumors, however the identity and roles of many of the soluble factors these macrophages produce remains to be elucidated in detail. In addition to producing angiogenic factors (e.g. VEGF), proteases (e.g. MMP9) and immunomodulatory factors (e.g. IL10) which, by modifying the local microenvironment, likely contribute to progression in the majority of solid tumors, we have evaluated the extent to which macrophage cytokines may differentially affect distinct breast cancer subtypes. We identified 23 cytokines produced in a culture model of human tumor-associated macrophages and report that basal and luminal breast cancer cell lines express different repertoires of receptors for these cytokines. These data suggest that tumor-associated macrophages make specific contributions to different breast cancer subtypes and that understanding the importance of these interactions will be crucial to developing subtype-specific therapies targeting the macrophage component of the breast tumor microenvironment.