Liquid biopsy in chronic liver disease.

Chronic liver diseases account for a considerable toll of incapacities, suffering, deaths, and resources of the nation's health systems. They can be prevented, treated or even cured when the diagnosis is made on time. Traditional liver biopsy remains the gold standard to diagnose liver diseases, but it has several limitations. Liquid biopsy is emerging as a superior alternative to surgical biopsy given that it surpasses the limitations: it is more convenient, readily and repeatedly accessible, safe, cheap, and provides a more detailed molecular and cellular representation of the individual patient's disease. Progress in understanding the molecular and cellular bases of diseased tissues and organs that normally release cells and cellular components into the bloodstream is catapulting liquid biopsy as a source of biomarkers for diagnosis, prognosis, and prediction of therapeutic response, thus supporting the realization of the promises of precision medicine. The review aims to summarize the evidence of the usefulness of liquid biopsy in liver diseases, including the presence of different biomarkers as circulating epithelial cells, cell-free nucleic acids, specific species of DNA and RNA, and the content of extracellular vesicles.

Origin of personalized medicine in pioneering, passionate, genomic research.

Personalized medicine, one of the main promises of the Human Genome Project (HGP) that began three decades ago, is now a new therapeutic paradigm. With its arrival the era of developing drugs to suit all patients, yet often having to withdraw a promising new one because a minority of patients was at risk, even though it had proved valuable for the majority was consigned to history as were trial-and-error strategies being the predominant means of tailoring therapy. But how did it originate and the earliest examples emerge? Is it true that the first personalized diagnostic test was the companion test for Herceptin®? This account of a remarkable journey from genomic and translational research to therapeutic and diagnostic innovations, describes how sequencing the human growth hormone (hGH) locus provided proof of principle for HGP-inspired personalized medicine. Sequencing this locus and the resultant biomanufacture of HGH and the development of a test capable of detecting which patients would benefit from its administration helped silence the skeptics who questioned the validity of such an approach. The associated companion diagnostic was created four years before the invention of the HercepTest® (registered as the first companion diagnostics ever developed). By cultivating genomic research with passion and pursuing its applications, we and many others contributed to the emergence of a new diagnostics industry, the discovery of better actionable gene-targets and to a revitalized pharmaceutical industry capable of developing safer and more effective therapies. In combination, these developments are beginning to fulfill the promise of the HGP, offering each patient the opportunity to adopt the right treatment at the correct dosage in an opportune manner.

Complete Screening of Exons 2, 3, and 4 of KRAS and NRAS Genes Reveals a Higher Number of Clinically Relevant Mutations than Food and Drug Administration Quantitative Polymerase Chain Reaction-Based Commercial Kits.

BACKGROUND: The presence of clinically relevant mutations in KRAS and NRAS genes determines the response of anti-epidermal growth factor receptor antibody therapy for metastatic colorectal cancer (mCRC). The only quantitative polymerase chain reaction (qPCR)-based diagnostic tests approved by the Food and Drug Administration (FDA) screen merely for mutations in codons 12 and 13 of KRAS. OBJECTIVE: The objective of the study was to study the frequency of clinically relevant mutations in KRAS and NRAS genes that are not included in FDA-approved qPCR tests. METHODS: Formalin-fixed paraffin-embedded tumor specimens from 1113 mCRC Mexican patients from different health institutions across the country were analyzed by Sanger sequencing for KRAS mutations in exons 2, 3, and 4. Furthermore, 83 were analyzed in exons 2, 3, and 4 of NRAS. RESULTS: From the specimens tested for KRAS, 33.69% harbored a mutation. From these, 71.77% were in codon 12 and 27.69% in codon 13 (both located in exon 2). Codons 59 (exon 3) and 146 (exon 4) accounted for the remaining 0.54%. From the 83 specimens, in which NRAS was analyzed, three mutations were found in codon 12 (3.61%). Approximately 6% of RAS mutated specimens would have been falsely reported as RAS wild type if an FDA-approved qPCR diagnostic test had been used. CONCLUSIONS: While these kits based on qPCR can be very practical and highly sensitive, their mutation coverage ignores mutations from poorly genetically characterized populations.

Gene Expression during BTEX Biodegradation by a Microbial Consortium Acclimatized to Unleaded Gasoline and a Pseudomonas putida Strain (HM346961) Isolated from It.

Pseudomonas putida strain (HM346961) was isolated from a consortium of bacteria acclimatized to unleaded gasoline-contaminated water. The consortium can efficiently remove benzene, toluene, ethylbenzene and xylene (BTEX) isomers, and a similar capability was observed with the P. putida strain. Proteome of this strain showed certain similarities with that of other strains exposed to the hydrocarbon compounds. Furthermore, the toluene di-oxygenase (tod) gene was up-regulated in P. putida strain when exposed to toluene, ethylbenzene, xylene, and BTEX. In contrast, the tod gene of P. putida F1 (ATCC 700007) was up-regulated only in the presence of toluene and BTEX. Several differences in the nucleotide and protein sequences of these two tod genes were observed. This suggests that tod up-regulation in P. putida strain may partially explain their great capacity to remove aromatic compounds, relative to P. putida F1. Therefore, new tod and P. putida strain are promising for various environmental applications.

A pharmacogenetic pilot study reveals MTHFR, DRD3, and MDR1 polymorphisms as biomarker candidates for slow atorvastatin metabolizers.

BACKGROUND: The genetic variation underlying atorvastatin (ATV) pharmacokinetics was evaluated in a Mexican population. Aims of this study were: 1) to reveal the frequency of 87 polymorphisms in 36 genes related to drug metabolism in healthy Mexican volunteers, 2) to evaluate the impact of these polymorphisms on ATV pharmacokinetics, 3) to classify the ATV metabolic phenotypes of healthy volunteers, and 4) to investigate a possible association between genotypes and metabolizer phenotypes. METHODS: A pharmacokinetic study of ATV (single 80-mg dose) was conducted in 60 healthy male volunteers. ATV plasma concentrations were measured by high-performance liquid chromatography mass spectrometry. Pharmacokinetic parameters were calculated by the non-compartmental method. The polymorphisms were determined with the PHARMAchip® microarray and the TaqMan® probes genotyping assay. RESULTS: Three metabolic phenotypes were found in our population: slow, normal, and rapid. Six gene polymorphisms were found to have a significant effect on ATV pharmacokinetics: MTHFR (rs1801133), DRD3 (rs6280), GSTM3 (rs1799735), TNFα (rs1800629), MDR1 (rs1045642), and SLCO1B1 (rs4149056). The combination of MTHFR, DRD3 and MDR1 polymorphisms associated with a slow ATV metabolizer phenotype. CONCLUSION: Further studies using a genetic preselection method and a larger population are needed to confirm these polymorphisms as predictive biomarkers for ATV slow metabolizers. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12614000851662, date registered: August 8, 2014.

Findings and Challenges in Replacing Traditional Uterine Cervical Cancer Diagnosis with Molecular Tools in Private Gynecological Practice in Mexico.

We have been encouraging practicing gynecologists to adopt molecular diagnostics tests, PCR, and cancer biomarkers, as alternatives enabled by these platforms, to traditional Papanicolaou and colposcopy tests, respectively. An aliquot of liquid-based cytology was used for the molecular test [high-risk HPV types, (HR HPV)], another for the PAP test, and one more for p16/Ki67 dual-stain cytology. A total of 4499 laboratory samples were evaluated, and we found that 25.1% of low-grade samples and 47.9% of high-grade samples after PAP testing had a negative HR HPV-PCR result. In those cases, reported as Pap-negative, 22.1% had a positive HR HPV-PCR result. Dual staining with p16/Ki67 biomarkers in samples was positive for HR HPV, and 31.7% were also positive for these markers. Out of the PCR results that were positive for any of these HR HPV subtypes, n 68.3%, we did not find evidence for the presence of cancerous cells, highlighting the importance of performing dual staining with p16/Ki67 after PCR to avoid unnecessary colposcopies. The encountered challenges are a deep-rooted social reluctance in Mexico to abandon traditional Pap smears and the opinion of many specialists. Therefore, we still believe that colposcopy continues to be a preferred procedure over the dual-staining protocol.

Gene Content and Coding Diversity of the Growth Hormone Loci of Apes.

The growth hormone (GH) locus has experienced a dramatic evolution in primates, becoming multigenic and diverse in anthropoids. Despite sequence information from a vast number of primate species, it has remained unclear how the multigene family was favored. We compared the structure and composition of apes' GH loci as a prerequisite to understanding their origin and possible evolutionary role. These thorough analyses of the GH loci of the chimpanzee, gorilla, and orangutan were done by resorting to previously sequenced bacterial artificial chromosomes (BACs) harboring them, as well as to their respective genome projects data available in GenBank. The GH loci of modern man, Neanderthal, gibbon, and wild boar were retrieved from GenBank. Coding regions, regulatory elements, and repetitive sequences were identified and compared among species. The GH loci of all the analyzed species are flanked by the genes CD79B (5') and ICAM-1 (3'). In man, Neanderthal, and chimpanzee, the loci were integrated by five almost indistinguishable genes; however, in the former two, they rendered three different hormones, and in the latter, four different proteins were derived. Gorilla exhibited six genes, gibbon seven, and orangutan four. The sequences of the proximal promoters, enhancers, P-elements, and a locus control region (LCR) were highly conserved. The locus evolution might have implicated duplications of the ancestral pituitary gene (GH-N) and subsequent diversification of the copies, leading to the placental single GH-V gene and the multiple CSH genes.

Mesenchymal Stem Cell Therapies Approved by Regulatory Agencies around the World.

Cellular therapy has used mesenchymal stem cells (MSCs), which in cell culture are multipotent progenitors capable of producing a variety of cells limited to the mesoderm layer. There are two types of MSC sources: (1) adult MSCs, which are obtained from bone marrow, adipose tissue, peripheral blood, and dental pulp; and (2) neonatal-tissue-derived MSCs, obtained from extra-embryonic tissues such as the placenta, amnion, and umbilical cord. Until April 2023, 1120 registered clinical trials had been using MSC therapies worldwide, but there are only 12 MSC therapies that have been approved by regulatory agencies for commercialization. Nine of the twelve MSC-approved products are from Asia, with Republic of Korea being the country with the most approved therapies. In the future, MSCs will play an important role in the treatment of many diseases. However, there are many issues to deal with before their application and usage in the medical field. Some strategies have been proposed to face these problems with the hope of reaching the objective of applying these MSC therapies at optimal therapeutic levels.

Factors Associated with Malnutrition Risk in Residents of Long-Term Care Facilities in Mexico.

OBJECTIVE: To investigate factors associated with the nutritional status in institutionalized Mexican older adults. MATERIAL AND METHODS: In this cross-sectional study of residents in three long-term care facilities (LTCFs) in Monterrey, Mexico, a medical history, Mini-Mental State Examination, Barthel index, and geriatric depression scale, and Mini Nutritional Assessment (MNA) were performed. Risk of malnutrition and malnutrition status were defined as MNA 17-23.5 and <17, respectively. RESULTS: Residents (n = 280) had a median age of 85 years and 72.1% were female. A total of 116 (41.4%) were at risk of malnutrition and 35 (12.5%) were malnourished. Having malnutrition or being at risk of malnutrition was associated with age (OR = 1.048), functional dependence (OR = 8.376), body mass index (BMI) <22 (OR = 7.518), cognitive impairment (OR = 2.210), urinary incontinence (OR = 2.397), previous stroke (OR = 2.870), Parkinson's disease (OR = 5.193), use of calcium channel blockers (OR = 3.706), and use of atypical antipsychotics (OR = 2.277). Having benign prostatic hyperplasia (OR = 0.067) or the use of angiotensin II receptor blockers (OR = 0.038) were related to being well-nourished. CONCLUSIONS: In a population of residents of three LTCFs in Mexico, we found a high prevalence of malnutrition or being at risk of malnutrition. This underscores the need to implement guidelines for the prompt identification of this condition and further explanation of the factors identified as possibly related to malnutrition.

Framework for Adoption of Next-Generation Sequencing (NGS) Globally in the Oncology Area.

Radical new possibilities of improved treatment of cancer are on offer from an advanced medical technology already demonstrating its significance: next-generation sequencing (NGS). This refined testing provides unprecedentedly precise diagnoses and permits the use of focused and highly personalized treatments. However, across regions globally, many cancer patients will continue to be denied the benefits of NGS as long as some of the yawning gaps in its implementation remain unattended. The challenges at the regional and national levels are linked because putting the solutions into effect is highly dependent on cooperation between regional- and national-level cooperation, which could be hindered by shortfalls in interpretation or understanding. The aim of the paper was to define and explore the necessary conditions for NGS and make recommendations for effective implementation based on extensive exchanges with policy makers and stakeholders. As a result, the European Alliance for Personalised Medicine (EAPM) developed a maturity framework structured around demand-side and supply-side issues to enable interested stakeholders in different countries to self-evaluate according to a common matrix. A questionnaire was designed to identify the current status of NGS implementation, and it was submitted to different experts in different institutions globally. This revealed significant variability in the different aspects of NGS uptake. Within different regions globally, to ensure those conditions are right, this can be improved by linking efforts made at the national level, where patients have needs and where care is delivered, and at the global level, where major policy initiatives in the health field are underway or in preparation, many of which offer direct or indirect pathways for building those conditions. In addition, in a period when consensus is still incomplete and catching up is needed at a political level to ensure rational allocation of resources-even within individual countries-to enable the best ways to make the necessary provisions for NGS, a key recommendation is to examine where closer links between national and regional actions could complement, support, and mutually reinforce efforts to improve the situation for patients.

Empowering quality data - the Gordian knot of bringing real innovation into healthcare system.

OBJECTIVES: The introduction of Personalised Medicine (PM) into healthcare systems could benefit from a clearer understanding of the distinct national and regional frameworks around the world. Recent engagement by international regulators on maximising the use of real-world evidence (RWE) has highlighted the scope for improving the exploitation of the treasure-trove of health data that is currently largely neglected in many countries. The European Alliance for Personalised Medicine (EAPM) led an international study aimed at identifying the current status of conditions. METHODS: A literature review examined how far such frameworks exist, with a view to identifying conducive factors - and crucial gaps. This extensive review of key factors across 22 countries and 5 regions revealed a wide variety of attitudes, approaches, provisions and conditions, and permitted the construction of a comprehensive overview of the current status of PM. Based on seven key pillars identified from the literature review and expert panels, the data was quantified, and on the basis of further analysis, an index was developed to allow comparison country by country and region by region. RESULTS: The results show that United States of America is leading according to overall outcome whereas Kenya scored the least in the overall outcome. CONCLUSIONS: Still, common approaches exist that could help accelerate take-up of opportunities even in the less prosperous parts of the world.

Amino acid substitutions in human growth hormone affect secondary structure and receptor binding.

The interaction between human Growth Hormone (hGH) and hGH Receptor (hGHR) has basic relevance to cancer and growth disorders, and hGH is the scaffold for Pegvisomant, an anti-acromegaly therapeutic. For the latter reason, hGH has been extensively engineered by early workers to improve binding and other properties. We are particularly interested in E174 which belongs to the hGH zinc-binding triad; the substitution E174A is known to significantly increase binding, but to now no explanation has been offered. We generated this and several computationally-selected single-residue substitutions at the hGHR-binding site of hGH. We find that, while many successfully slow down dissociation of the hGH-hGHR complex once bound, they also slow down the association of hGH to hGHR. The E174A substitution induces a change in the Circular Dichroism spectrum that suggests the appearance of coiled-coiling. Here we show that E174A increases affinity of hGH against hGHR because the off-rate is slowed down more than the on-rate. For E174Y (and certain mutations at other sites) the slowdown in on-rate was greater than that of the off-rate, leading to decreased affinity. The results point to a link between structure, zinc binding, and hGHR-binding affinity in hGH.

The chimpanzee GH locus: composition, organization, and evolution.

In most mammals the growth hormone (GH) locus comprises a single gene expressed primarily in the anterior pituitary gland. However, in higher primates multiple duplications of the GH gene gave rise to a complex locus containing several genes. In man this locus comprises five genes, including GH-N (expressed in pituitary) and four genes expressed in the placenta, but in other species the number and organization of these genes vary. The situation in chimpanzee has been unclear, with suggestions of up to seven GH-like genes. We have re-examined the GH locus in chimpanzee and have deduced the complete sequence. The locus includes five genes apparently organized in a fashion similar to that in human, with two of these genes encoding GH-like proteins, and three encoding chorionic somatomammotropins/placental lactogens (CSHs/PLs). There are notable differences between the human and chimpanzee loci with regard to the expressed proteins, gene regulation, and gene conversion events. In particular, one human gene (hCSH-L) has changed substantially since the chimpanzee/human split, potentially becoming a pseudogene, while the corresponding chimpanzee gene (CSH-A1) has been conserved, giving a product almost identical to the adjacent CSH-A2. Chimpanzee appears to produce two CSHs, with potentially differing biological properties, whereas human produces a single CSH. The pattern of gene conversion in human has been quite different from that in chimpanzee. The region around the GH-N gene in chimpanzee is remarkably polymorphic, unlike the corresponding region in human. The results shed new light on the complex evolution of the GH locus in higher primates.

Fighting Cancer around the World: A Framework for Action.

Tackling cancer is a major challenge right on the global level. Europe is only the tip of an iceberg of cancer around the world. Prosperous developed countries share the same problems besetting Europe-and the countries and regions with fewer resources and less propitious conditions are in many cases struggling often heroically against a growing tide of disease. This paper offers a view on these geographically wider, but essentially similar, challenges, and on the prospects for and barriers to better results in this ceaseless battle. A series of panels have been organized by the European Alliance for Personalised Medicine (EAPM) to identify different aspects of cancer care around the globe. There is significant diversity in key issues such as NGS, RWE, molecular diagnostics, and reimbursement in different regions. In all, it leads to disparities in access and diagnostics, patients' engagement, and efforts for a better understanding of cancer.

Personalized Medicine in Ovarian Cancer: A Perspective From Mexico.

Ovarian cancer (OC) represents a serious health problem worldwide. In Mexico, most OC patients are detected at late stages, consequently making OC one of the leading causes of death in women after reaching puberty. Personalized medicine (PM) provides an individualized therapeutic opportunity for treating each patient relying on "omic" tools to match the correct drug with the specific pathogenic genomic signature. PM can help predict the best therapeutic option for each affected woman suffering from OC. In recent years, Mexico has made contributions to the PM of OC; however, it still has a long way to go for its full implementation in the country's health system.

Mesenchymal Stem Cells Current Clinical Applications: A Systematic Review.

INTRODUCTION: Human Mesenchymal Stem Cells (hMSCs) are multipotent stem cells capable of renewing themselves and differentiation in vitro into different kinds of tissues. In vivo hMSCs are sources of trophic factors modulating the immune system and inducing intrinsic stem cells to repair damaged tissues. Currently, there are multiple clinical trials (CT) using hMSCs for therapeutic purposes in a large number of clinical settings. MATERIAL AND METHODS: The search strategy on clinicaltrials.gov has focused on the key term "Mesenchymal Stem Cells", and the inclusion and exclusion criteria were separated into two stages. Stage 1, CT on phases 1-4: location, the field of application, phase, and status. For stage 2, CT that have published outcome results: field of application, treatment, intervention model, source, preparation methods, and results. RESULTS: By July 2020, there were a total of 1,138 registered CT. Most studies belong to either phase 2 (61.0%) or phase 1 (30.8%); most of them focused in the fields of traumatology, neurology, cardiology, and immunology. Only 18 clinical trials had published results: the most common source of isolation was bone marrow; the treatment varied from 1-200 M hMSCs; all of them have similar preparation methods; all of them have positive results with no serious adverse effects. CONCLUSIONS: There appears to be a broad potential for the clinical use of hMSCs with no reported serious adverse events. There are many trials in progress, their future results will help to explore the therapeutic potential of these promising cellular sources of medicinal signals.

Multiple HPV Infections and Viral Load Association in Persistent Cervical Lesions in Mexican Women.

Persistent high-risk human papillomavirus (HR-HPV) infections play a major role in the development of invasive cervical cancer (CC), and screening for such infections is in many countries the primary method of detecting and preventing CC. HPV typing can be used for triage and risk stratification of women with atypical squamous cells of undetermined significance (ASC-US)/low-grade cervical lesions (LSIL), though the current clinical practice in Mexico is to diagnose CC or its preceding conditions mainly via histology and HR-HPV detection. Additional information regarding these HPV infections, such as viral load and co-infecting agents, might also be useful for diagnosing, predicting, and evaluating the possible consequences of the infection and of its prevention by vaccination. The goal of this follow-up hospital case study was to determine if HPV types, multiple HPV infections, and viral loads were associated with infection persistence and the cervical lesion grade. A total of 294 cervical cytology samples drawn from patients with gynecological alterations were used in this study. HPV types were identified by real-time PCR DNA analysis. A subset of HPV-positive patients was reevaluated to identify persistent infections. We identified HPV types 16, 18, and 39 as the most prevalent. One hundred five of the patients (59%) were infected with more than one type of HPV. The types of HPV associated with multiple HPV infections were 16, 18, and 39. In the follow-up samples, 38% of patients had not cleared the initially detected HPV infection, and these were considered persistent. We found here an association between multiple HPV infections and high viral loads with and infection persistence. Our findings suggest there are benefits in ascertaining viral load and multiple HPV infections status of HR-HPV infections for predicting the risk of persistence, a requirement for developing CC. These findings contribute to our understanding of HPV epidemiology and may allow screening programs to better assess the cancer-developing risks associated with individual HR-HPV infections.

Acetylsalicylic acid inhibits hepatitis C virus RNA and protein expression through cyclooxygenase 2 signaling pathways.

UNLABELLED: It has been reported that salicylates (sodium salicylate and aspirin) inhibit the replication of flaviviruses, such as Japanese encephalitis virus and dengue virus. Therefore, we considered it important to test whether acetylsalicylic acid (ASA) had anti-hepatitis C virus (HCV) activity. To this end, we examined the effects of ASA on viral replication and protein expression, using an HCV subgenomic replicon cell culture system. We incubated Huh7 replicon cells with 2-8 mM ASA for different times and measured HCV-RNA and protein levels by northern blot, real-time polymerase chain reaction, and western analysis, respectively. We found that ASA had a suppressive effect on HCV-RNA and protein levels (nearly 58%). ASA-dependent inhibition of HCV expression was not mediated by the 5'-internal ribosome entry site or 3'-untranslated regions, as determined by transfection assays using bicistronic constructs containing these regulatory regions. However, we found that HCV-induced cyclooxygenase 2 (COX-2) messenger RNA and protein levels and activity and these effects were down-regulated by ASA, possibly by a nuclear factor kappa B-independent mechanism. We also observed that the ASA-dependent inhibition of viral replication was due in part to inhibition of COX-2 and activation of p38 and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 (MEK1/2) mitogen-activated protein kinases (MAPKs). Inhibition of these kinases by SB203580 and U0126, respectively, and by short interfering RNA silencing of p38 and MEK1 MAPK prevented the antiviral effect of ASA. Taken together, our findings suggest that the anti-HCV effect of ASA in the Huh7 replicon cells is due to its inhibitory effect on COX-2 expression, which is mediated in part by the activation of MEK1/2/p38 MAPK. CONCLUSION: These findings suggest the possibility that ASA could be an excellent adjuvant in the treatment of chronic HCV infection.

Comparison of Automated and Manual DNA Isolation Methods of Liquid-Based Cytology Samples.

Liquid-based cytology (LBC) has been used as a diagnostic tool for cervical cancer for years and is now being adopted for other gynecological cancers. LBC represents an important challenge to ensure that the process yields representative biospecimens for quality control (QC) of diagnostic procedures. In this study, we compare QC parameters (integrity, yield and purity, and polymerase chain reaction [PCR] amplification) of DNA isolated from LBC (N = 296) using two different nucleic acid isolation methods, manual (n = 233) or automated (n = 63). We also evaluated two different types of cytological brushes for sampling from the cervix. Our results suggest that manual isolation (yield 22.81 ± 1.92 µg) resulted in increased DNA recovery when compared with automated isolation (yield 9.96 ± 1.11 µg) from LBC samples, with a p-value of <0.0003. We estimated that 98% (53/54) of the samples preserved the integrity of DNA and were suitable for standard molecular biology analyses. The ß-globin gene was amplified in 100% (296/296) of the DNA samples by endpoint PCR. We found no significant difference between the performance of the cytological brushes (p value of <0.6711) in a general overview. However, when looking at the results from using each brush individually, the manual isolation method was statistically superior to the automated method. Our work illustrates the impact of good QC of preanalytic conditions, which will be important for the application of LBC for developing early detection methods for gynecological cancers.

C3435T polymorphism in the MDR1 gene and breast cancer risk in northeastern Mexico.

The multidrug resistance gene 1 (MDR1) encodes a membrane-bound phosphoglycoprotein (P-gp). It functions as a transmembrane efflux pump for various structurally unrelated carcinogens and toxins. Polymorphism C3435T of MDR1 has been investigated for its association with breast cancer in different populations. However, the results are inconsistent and inconclusive. The objective of this study was to determine whether an association exists between the MDR1 C3435T polymorphism and the risk of breast cancer in a population from northeastern Mexico, which displays ethnic characteristics that differentiate it from other populations of the country. Genotypes were determined for 243 women with histologically confirmed breast cancer and 118 control subjects. Polymorphism of MDR1 C3435T was analyzed by DNA microarray. We found an increased breast cancer risk associated with CT and CC genotypes (OR = 1.88, 95% CI: 1.04-3.39, P = 0.033 for CT vs. TT; OR = 2.91, 95% CI: 1.48-5.74, P = 0.001 for CC vs. TT). Furthermore, there was significantly increased risk of breast cancer associated with the C allele (OR = 1.59, 95% CI: 1.16-2.18, P = 0.003). In conclusion, we found an association between the MDR1 C3435T polymorphism and risk of breast cancer in subjects from northeastern Mexico. Identification of inter-individual variability in this polymorphism may be useful for individualizing breast cancer genetic screening and therapeutic intervention.