Taja-Chayeb L.,National Cancer Institute of Mexico |
Agundez J.A.,University of Extremadura |
Miguez-Munoz C.,National Cancer Institute of Mexico |
Chavez-Blanco A.,National Cancer Institute of Mexico |
Duenas-Gonzalez A.,National Autonomous University of Mexico
Genetics and Molecular Research | Year: 2012
The acetylating activity of N-acetyltransferase 2 (NAT2) has critical implications for therapeutics and disease susceptibility. To date, several polymorphisms that alter the enzymatic activity and/or protein stability of NAT2 have been identified. We examined the distribution and frequency of NAT2 genotypes in the Mexican population. Among 250 samples amplified and sequenced for the NAT2 gene, we found seven different SNPs; the most frequent allele was 803 A>G (35.8%), followed by 282 C>T, 341 T>C, and 481 C>T. There were no differences in the distribution of SNPs between healthy subjects and cancer patients. These eight polymorphisms defined 26 diplotypes; 11.6% were wild type (NAT2*4/NAT2*4), while the most common diplotype was NAT2*4/NAT2*5B, present in 17.2%. We did not identify other common polymorphisms. The results were compared with the NAT2 SNPs reported from other populations. All but the Turkish population was significantly different from ours. We conclude that the mixed-race Mexican population requires special attention because NAT2 genotype frequencies differ from those in other regions of the world. © FUNPEC-RP.
Malignant gastrointestinal neuroectodermal tumor: Clinicopathologic, immunohistochemical, ultrastructural, and molecular analysis of 16 cases with a reappraisal of clear cell sarcoma-like tumors of the gastrointestinal tract
Stockman D.L.,Medical College of Wisconsin |
Miettinen M.,Armed Forces Institute of Pathology |
Suster S.,Medical College of Wisconsin |
Spagnolo D.,University of Western Australia |
And 7 more authors.
American Journal of Surgical Pathology | Year: 2012
The clinical, histologic, immunophenotypic, ultrastructural, and molecular features of a distinctive gastrointestinal tumor are described. Sixteen patients, 8 women and 8 men aged 17 to 77 years (mean age, 42 y; 63% less than 40 y) presented with abdominal pain, intestinal obstruction, and an abdominal mass. Mean tumor size was 5.2 cm (range, 2.4 to 15.0 cm). The tumors arose in the small bowel (10), stomach (4), and colon (2) and were histologically characterized by a sheet-like or nested population of epithelioid or oval-to-spindle cells with small nucleoli and scattered mitoses. Five cases showed focal clearing of the cytoplasm. Scattered osteoclast-type multinucleated giant cells were present in 8 cases. The tumor cells were positive for S-100 protein, SOX10, and vimentin in 100% of cases, for CD56 in 70%, for synaptophysin in 56%, for NB84 in 50%, for NSE in 45%, and for neurofilament protein in 14% of cases. All cases tested were negative for specific melanocytic, gastrointestinal stromal tumors, epithelial, and myoid markers. Ultrastructural examination of 5 cases showed features of primitive neuroectodermal cells with clear secretory vesicles, dense-core granules, occasional gap junctions, and no evidence of melanogenesis. EWSR1 gene rearrangement was assessed by fluorescence in situ hybridization in 14 cases. Twelve cases (86%) showed split EWSR1 signal consistent with a chromosomal translocation involving EWSR1. One case showed extra intact signals, indicating that the nuclei possessed either extra copies of the EWSR1 gene or chromosome 22 polysomy. Only 1 case showed no involvement of the EWSR1 gene. Six cases demonstrated rearrangement of the partner fusion gene ATF1 (46%), and 3 showed rearrangement of CREB1 (23%); 2 cases lacked rearrangement of either partner gene. Clinical follow-up was available in 12 patients and ranged from 1.5 to 106 months. Six patients died of their tumors (mean survival, 32 mo; 83% less than 24 mo). At last follow-up, 4 patients were alive with regional, lymph node, and liver metastases, and 2 patients were alive with no evidence of disease. The tumor described here is an aggressive form of neuroectodermal tumor that should be separated from other primitive epithelioid and spindle cell tumors of the gastrointestinal tract. The distinctive ultrastructural features and absence of melanocytic differentiation serve to separate them from soft tissue clear cell sarcomas involving the gastrointestinal tract. The designation "malignant gastrointestinal neuroectodermal tumor" is proposed for this tumor type. © 2012 by Lippincott Williams & Wilkins.
Portenoy R.K.,Beth Israel Deaconess Medical Center |
Ganae-Motan E.D.,Hospital Sf Ioan Cel Nou |
Allende S.,National Cancer Institute of Mexico |
Yanagihara R.,Hazel Hawkins Hospital |
And 5 more authors.
Journal of Pain | Year: 2012
Patients with advanced cancer who have pain that responds poorly to opioid therapy pose a clinical challenge. Nabiximols (Nabiximols is the US Adopted Name [USAN] for Sativex [GW Pharma Ltd, Wiltshire, UK], which does not yet have an INN), a novel cannabinoid formulation, is undergoing investigation as add-on therapy for this population. In a randomized, double-blind, placebo-controlled, graded-dose study, patients with advanced cancer and opioid-refractory pain received placebo or nabiximols at a low dose (1-4 sprays/day), medium dose (6-10 sprays/day), or high dose (11-16 sprays/day). Average pain, worst pain and sleep disruption were measured daily during 5 weeks of treatment; other questionnaires measured quality of life and mood. A total of 360 patients were randomized; 263 completed. There were no baseline differences across groups. The 30% responder rate primary analysis was not significant for nabiximols versus placebo (overall P =.59). A secondary continuous responder analysis of average daily pain from baseline to end of study demonstrated that the proportion of patients reporting analgesia was greater for nabiximols than placebo overall (P =.035), and specifically in the low-dose (P =.008) and medium-dose (P =.039) groups. In the low-dose group, results were similar for mean average pain (P =.006), mean worst pain (P =.011), and mean sleep disruption (P =.003). Other questionnaires showed no significant group differences. Adverse events were dose-related and only the high-dose group compared unfavorably with placebo. This study supports the efficacy and safety of nabiximols at the 2 lower-dose levels and provides important dose information for future trials. Perspective: Nabiximols, a novel cannabinoid formulation, may be a useful add-on analgesic for patients with opioid-refractory cancer pain. A randomized, double-blind, placebo-controlled, graded-dose study demonstrated efficacy and safety at low and medium doses. © 2012 by the American Pain Society.
Arrieta O.,National Cancer Institute of Mexico |
Arrieta O.,Experimental Oncology Laboratory |
Ramirez-Tirado L.-A.,Experimental Oncology Laboratory |
Baez-Saldana R.,National Institute of Respiratory Diseases Ismael Cosio Villegas |
And 3 more authors.
Lung Cancer | Year: 2015
Objective: Sixteen percent of US population is Hispanic, mostly Mexican. Recently, two independent American reports demonstrated a higher overall survival (OS) in Hispanic populations compared with non-Hispanic-white populations (NHW) with non-small-cell lung cancer (NSCLC), even when most Hispanic patients are diagnosed at advanced disease stages and have lower income status. We analyzed the clinical, pathological, and molecular characteristics as well as outcomes in a cohort of NSCLC Hispanic patients from the National Cancer Institute of Mexico that could explain this "Hispanic Paradox". Material and methods: A cohort of 1260 consecutive NSCLC patients treated at the National Cancer Institute of Mexico from 2007 to 2014 was analyzed. Their clinical-pathological characteristics, the presence of EGFR and KRAS mutations and the prognosis were evaluated. Results: Patients presented with disease stages II, IIIa, IIIb and IV at rates of 0.6, 4.8, 18.4 and 76.3%, respectively. NSCLC was associated with smoking in only 56.5% of the patients (76.7% of male vs. 33.0% of female patients). Wood smoke exposure (WSE) was associated with 37.2% of the cases (27.3% in men vs. 48.8% in women). The frequency of EGFR mutations was 27.0% (18.5% in males vs. 36.9% in females, p <. 0.001) and the frequency for KRAS mutations was 10.5% (10.3% men vs. 10.1% in women p = 0.939). The median OS for all patients was 23.0 [95% CI 19.4-26.2], whereas for patients at stage IV, it was 18.5 months [95% CI 15.2-21.8]. The independent factors associated with the OS were the ECOG, disease stage, EGFR and KRAS mutation status. Conclusion: The high frequency of EGFR mutations and low frequency of KRAS mutations in Hispanic populations and different prevalence in lung cancer-related-developing risk factors compared with Caucasian populations, such as the lower frequency of smoking exposure and higher WSE, particularly in women, might explain the prognosis differences between foreign-born-Hispanics, US-born-Hispanics and NHWs. © 2015 Elsevier Ireland Ltd.
Peralta-Zaragoza O.,National Health Research Institute |
Bermudez-Morales V.H.,National Health Research Institute |
Perez-Plasencia C.,National Cancer Institute of Mexico |
Perez-Plasencia C.,National Autonomous University of Mexico |
And 3 more authors.
OncoTargets and Therapy | Year: 2012
Cervical cancer is the second most common cause of cancer death in women world- wide and the development of new diagnosis, prognostic, and treatment strategies merits special attention. Although surgery and chemoradiotherapy can cure 80%-95% of women with early stage cancer, the recurrent and metastatic disease remains a major cause of cancer death. Many efforts have been made to design new drugs and develop gene therapies to treat cervical cancer. In recent decades, research on treatment strategies has proposed several options, including the role of HPV E6 and E7 oncogenes, which are retained and expressed in most cervical cancers and whose respective oncoproteins are critical to the induction and maintenance of the malignant phenotype. Other efforts have been focused on antitumor immunotherapy strategies. It is known that during the development of cervical cancer, a cascade of abnormal events is induced, including disruption of cellular cycle control, perturbation of antitumor immune response, alteration of gene expression, and deregulation of microRNA expression. Thus, in this review article we discuss potential targets for the treatment of cervical cancer associated with HPV infection, with special attention to immunotherapy approaches, clinical trials, siRNA molecules, and their implications as gene therapy strategies against cervical cancer development © 2012 Peralta-Zaragoza et al, publisher and licensee Dove Medical Press Ltd.
PubMed | National Cancer Institute of Mexico, Juarez Autonomous University of Tabasco and Obstetrics and Gynecology Clinic
Type: Journal Article | Journal: Journal of medical virology | Year: 2015
Cervical cancer development has been mainly associated with persistent human papillomavirus (HPV) infections. However, HPV infection is unlikely to be sufficient to cause cervical cancer, and the contribution of other sexually transmitted infections (STIs) could be the determining factor for cervical lesion-progression. The aim of this study was to estimate the prevalence of STIs associated with HPV-positivity in 201 cervical samples from patients who underwent annual routine gynecological exams. The overall prevalence of STIs was 57.7%, and the most frequent infection was Ureaplasma spp (UP) (39.8%), followed by Gardnerella vaginalis (GV) (25.9%), -HPV (18.4%), Chlamydia trachomatis (CT) (1.5%), and Mycoplasma genitalium (MG) (0.5%). The highest prevalence rate of multiple non-HPV infections was observed for the age-range 31-40; for papillomavirus infection, the age-range was 21-30. In normal cervical samples, HPV16 was the most prevalent genotype (24.3%), followed by genotypes 58 (13.5%) and 52 (10.8%). Intriguingly, HPV18 was not detected in the study population, and genotypes 52 and 58 were found exclusively in samples with abnormal cytology. Papillomavirus infection with oncogenic types was significantly associated with GV (P=0.025) and strongly associated with multiple non-HPV pathogens (P=0.002). The following variables correlated significantly with cytological diagnosis of low-grade squamous intraepithelial lesion (LSIL): GV (P=0.028), multiple non-HPV infections (P=0.001), and high-risk HPV positivity (P=0.001). Epidemiological data from this study will contribute to the molecular detection of sexually transmitted pathogens from screening programs to identify those women who are at risk for developing cervical lesions.
PubMed | National Cancer Institute of Mexico, Research Center for Infectious Diseases and National Autonomous University of Mexico
Type: Journal Article | Journal: Oncology reports | Year: 2015
Cervical cancer (CC) is the third most diagnosed cancer among females worldwide and the fourth cause of cancer-related mortality. Prophylactic HPV vaccines and traditional pap-smear screening are undoubtedly capable of decreasing the incidence and mortality of CC. However, a large number of females succumb to the disease each year due to late diagnosis and resistance to conventional treatments. Thus, it is necessary to identify new molecular markers to predict the clinical outcome and to design powerful treatments. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and are involved in the modulation of several cell pathways associated with progression from pre-malignant to invasive and metastatic disease, increasing tumor malignancy. The aim of this review was to summarize the recent data that describe the important role of miRNAS involved in CC in order to determine their potential as prognostic biomarkers and as therapy targets. Studies of >40 miRNAs with roles in cancer regulation were identified. We also identified 17 miRNAs associated with progression, 12 involved with clinical outcome and 7 that improved CC treatment response. The present review is expected to broaden understanding of the functional role and potential clinical uses of miRNAs in CC.
PubMed | National Institute of Genomic Medicine, National Cancer Institute of Mexico, Autonomous University of the State of Morelos, University of Santa María in Ecuador and Autonomous University of Guerrero
Type: | Journal: BMC cancer | Year: 2016
Expression of the microRNA miR-21 has been found to be altered in almost all types of cancers and it has been classified as an oncogenic microRNA or oncomir. Due to the critical functions of its target proteins in various signaling pathways, miR-21 is an attractive target for genetic and pharmacological modulation in various cancers. Cervical cancer is the second most common cause of death from cancer in women worldwide and persistent HPV infection is the main etiologic agent. This malignancy merits special attention for the development of new treatment strategies. In the present study we analyze the role of miR-21 in cervical cancer cells.To identify the downstream cellular target genes of upstream miR-21, we silenced endogenous miR-21 expression in a cervical intraepithelial neoplasia-derived cell lines using siRNAs. The effect of miR-21 on gene expression was assessed in cervical cancer cells transfected with the siRNA expression plasmid pSIMIR21. We identified the tumor suppressor gene PTEN as a target of miR-21 and determined the mechanism of its regulation throughout reporter construct plasmids. Using this model, we analyzed the expression of miR-21 and PTEN as well as functional effects such as autophagy and apoptosis induction.In SiHa cells, there was an inverse correlation between miR-21 expression and PTEN mRNA level as well as PTEN protein expression in cervical cancer cells. Transfection with the pSIMIR21 plasmid increased luciferase reporter activity in construct plasmids containing the PTEN-3-UTR microRNA response elements MRE21-1 and MRE21-2. The role of miR-21 in cell proliferation was also analyzed in SiHa and HeLa cells transfected with the pSIMIR21 plasmid, and tumor cells exhibited markedly reduced cell proliferation along with autophagy and apoptosis induction.We conclude that miR-21 post-transcriptionally down-regulates the expression of PTEN to promote cell proliferation and cervical cancer cell survival. Therefore, it may be a potential therapeutic target in gene therapy for cervical cancer.
PubMed | National Cancer Institute of Mexico, Juarez Autonomous University of Tabasco and National Autonomous University of Mexico
Type: Journal Article | Journal: Oncology reports | Year: 2015
The aim of the present study was to demonstrate that ribavirin, a known inhibitor of eIF4E and inosine 5-phosphate dehydrogenase (IMPDH), also inhibits histone methyltransferase zeste homolog 2 (EZH2). A computational searching revealed that ribavirin has a high structural similarity to 3-deazaneplanocin A (DZNep). The growth inhibitory effects of ribavirin as well as its effects upon epigenetic enzymes were evaluated in various cancer cell lines. siRNA assays were used to downregulate eIF4E, EZH2 and IMPDH to determine the contribution of these targets to the growth inhibitory effects of ribavirin. Ribavirin decreased EZH2 expression, inhibited histone methyltransferase activity and decreased H3K27 trimethylation. Ribavirin induced variable growth inhibition in a number of cell lines and downregulation of the targets, EZH2, eIF4E and IMPDH1 and 2 by siRNA led to comparable growth inhibition while no significant further reduction in viability was observed when siRNA transfected cells were treated with ribavirin. The results showed that ribavirin inhibits these cancer targets and should thus be studied for cancer therapy.
PubMed | National Cancer Institute of Mexico, National Institute of Genomic Medicine and University of Santa María in Ecuador
Type: | Journal: BioMed research international | Year: 2015
MicroRNAs and siRNAs belong to a family of small noncoding RNAs which bind through partial sequence complementarity to 3-UTR regions of mRNA from target genes, resulting in the regulation of gene expression. MicroRNAs have become an attractive target for genetic and pharmacological modulation due to the critical function of their target proteins in several signaling pathways, and their expression profiles have been found to be altered in various cancers. A promising technology platform for selective silencing of cell and/or viral gene expression using siRNAs is currently in development. Cervical cancer is the most common cancer in women in the developing world and sexually transmitted infection with HPV is the cause of this malignancy. Therefore, a cascade of abnormal events is induced during cervical carcinogenesis, including the induction of genomic instability, reprogramming of cellular metabolic pathways, deregulation of cell proliferation, inhibition of apoptotic mechanisms, disruption of cell cycle control mechanisms, and alteration of gene expression. Thus, in the present review article, we highlight new research on microRNA expression profiles which may be utilized as biomarkers for cervical cancer. Furthermore, we discuss selective silencing of HPV E6 and E7 with siRNAs which represents a potential gene therapy strategy against cervical cancer.