Héctor Aquiles Maldonado Martínez - Academia.edu (original) (raw)

Papers by Héctor Aquiles Maldonado Martínez

Pathology and Oncology Research, 2021

Background: Programmed cell death-ligand 1 (PD-L1) protein expression is one of the most extensiv... more Background: Programmed cell death-ligand 1 (PD-L1) protein expression is one of the most extensively studied biomarkers in patients with non-small cell lung cancer (NSCLC). However, there is scarce information regarding its association with distinct adenocarcinoma subtypes. This study evaluated the frequency of PD-L1 expression according to the IASLC/ATS/ERS classification and other relevant histological and clinical features. Patients and Methods: PD-L1 expression was assessed by immunohistochemistry (IHC). According to its positivity in tumor cells membrane, we stratified patients in three different tumor proportions score (TPS) cut-off points: a) <1% (negative), b) between 1 and 49%, and c) ≥50%; afterward, we analyzed the association among PD-L1 expression and lung adenocarcinoma (LADC) predominant subtypes, as well as other clinical features. As an exploratory outcome we evaluated if a PD-L1 TPS score ≥15% was useful as a biomarker for determining survival. Results: A total ...

Cancers

In triple-negative breast cancer (TNBC), only 30% of patients treated with neoadjuvant chemothera... more In triple-negative breast cancer (TNBC), only 30% of patients treated with neoadjuvant chemotherapy achieve a pathological complete response after treatment and more than 90% die due to metastasis formation. The diverse clinical responses and metastatic developments are attributed to extensive intrapatient genetic heterogeneity and tumor evolution acting on this neoplasm. In this work, we aimed to evaluate genomic alterations and tumor evolution in TNBC patients with aggressive disease. We sequenced the whole exome of 16 lesions from four patients who did not respond to therapy, and took several follow-up samples, including samples from tumors before and after treatment, as well as from the lymph nodes and skin metastases. We found substantial intrapatient genetic heterogeneity, with a variable tumor mutational composition. Early truncal events were MCL1 amplifications. Metastatic lesions had deletions in RB1 and PTEN, along with TERT, AKT2, and CCNE1 amplifications. Mutational sign...

Revista de investigación clínica; organo del Hospital de Enfermedades de la Nutrición

High-grade intraepithelial neoplasia (HGPIN) is the only lesion regarded as precursor of prostati... more High-grade intraepithelial neoplasia (HGPIN) is the only lesion regarded as precursor of prostatic carcinoma, though its frequency is unknown in many countries. Here we studied the frequency of HGPIN in a population with high grade frequency of prostatic carcinoma. A total of 486 cases of sextant prostatic biopsies performed from January 2001 to January 2006 were reviewed. These included 280 biopsies from patients belonging to an urban population, with medium or high socioeconomic status, from two hospitals in Mexico City. For comparison, 206 cases from the Regional Hospital of Tabasco located in the tropical zone of the country were included. This hospital receives patients from a rural population with low income and socioeconomic status. Of the total 486 cases, 162 (33.33%) cases were diagnosed as prostatic carcinoma and 319 (65.64%) as benign conditions. Only in five (1.03%) biopsies was HGPIN found. Three of these patients were from Mexico City, and two from the Regional Hospita...

Genes

Triple-negative breast cancer (TNBC) presents a marked diversity at the molecular level, which pr... more Triple-negative breast cancer (TNBC) presents a marked diversity at the molecular level, which promotes a clinical heterogeneity that further complicates treatment. We performed a detailed whole exome sequencing profile of 29 Mexican patients with long follow-up TNBC to identify genomic alterations associated with overall survival (OS), disease-free survival (DFS), and pathologic complete response (PCR), with the aim to define their role as molecular predictive factors of treatment response and prognosis. We detected 31 driver genes with pathogenic mutations in TP53 (53%), BRCA1/2 (27%), CDKN1B (9%), PIK3CA (9%), and PTEN (9%), and 16 operative mutational signatures. Moreover, tumors with mutations in BRCA1/2 showed a trend of sensitivity to platinum salts. We found an association between deficiency in DNA repair and surveillance genes and DFS. Across all analyzed tumors we consistently found a heterogeneous molecular complexity in terms of allelic composition and operative mutation...

The Journal of Molecular Diagnostics

Breast cancer is one of the leading causes of mortality in women worldwide, neoadjuvant chemother... more Breast cancer is one of the leading causes of mortality in women worldwide, neoadjuvant chemotherapy has emerged as an option for the management of locally advanced breast cancer. Extensive efforts have been made to identify new molecular markers to predict the response to neoadjuvant chemotherapy. Transcripts that do not encode proteins, termed lncRNAs, have been shown to display abnormal expression profiles in different types of cancer but their role as biomarkers in response to neoadjuvant chemotherapy has not been extensively studied. Herein, lncRNA expression was profiled using RNA-Seq in biopsies from patients who subsequently showed either response or no response to treatment. The GATA3-AS1 transcript was overexpressed in the nonresponder group and was the most stable feature when performing selection in multiple random forest models. GATA3-AS1 was experimentally validated by RT-qPCR in an extended group of 68 patients. Expression analysis confirmed that GATA3-AS1 is overexpressed primarily in patients who were nonresponsive to neoadjuvant chemotherapy with a sensitivity of 92.9%, specificity of 75.0% and an AUC of ∼0.90 as measured by ROC curve analysis. The statistical model based on Luminal B-like patients adjusted by menopausal status and phenotype (OR= 37.49; 95% CI= 6.74-208.42 P= 0.001), GATA3-AS1 was established as an independent predictor of response. Thus, lncRNA GATA3-AS1 is proposed as a potential predictive biomarker of nonresponse to neoadjuvant chemotherapy.

Turkish Journal of Surgery

Objective: Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors that express type 3 tyr... more Objective: Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors that express type 3 tyrosine kinase receptors and are thought to develop from the neoplastic transformation of the interstitial Cajal cells. The present study was performed to morphologically and immunohistologically evaluate GISTs, to compare their qualities using a GIST risk categorization system, and to identify the diagnostic and prognostic parameters of GISTs. Material and Methods: A total of 27 patients with GISTs underwent treatment and were followed up at the Gaziosmanpaşa Taksim Training and Research Hospital. Descriptive statistics was used to calculate the mean and median values. Survival analysis was performed by the Kaplan-Meier method. The analyses were performed using the SPSS version 22.0 software. Results: The mean follow-up time was 3.5 (5 months to 13 years) years. The mean age was 60.4 (29-82) years. The tumors were localized in the stomach (62.9%), extraintestinal areas (14.8%), intestine (7.4%), esophagus (7.4%), and rectum (7.4%). Twenty-four patients were classified according to the Fletcher system. Of these patients, 7 (25.9%) were classified as very low risk, 8 (29.6%) as low risk, 7 (25.9%) as intermediate risk, and 2 (7.4%) as high risk. Twenty-four patients underwent surgery. Of the 3 patients who did not undergo surgery, 1 had metastatic disease at the time of diagnosis, and 2 had mini-or micro-GISTs in the stomach. On endoscopic surveillance, all tumors remained stable. Three out of the 27 patients were lost to follow-up. Two patients developed recurrence, and 1 patient died of GIST. Conclusion: We analyzed the clinical and pathological characteristics of GIST. The most common site of tumor origin was the stomach. The size, mitotic index, and Ki-67 values were to be found high in intermediate-and high-risk groups and metastatic diseases.

Revista Mexicana de Ortodoncia

Facial asymmetry is one of the main findings during clinical practice with a prevalence between 2... more Facial asymmetry is one of the main findings during clinical practice with a prevalence between 21-85%; this causes both functional and aesthetic problems, and is manifested by an inconsistency in size, shape, or position of craniofacial structures on both sides of the mid-sagittal plane. Its etiology is attributed to hereditary and/ or environmental factors that may be expressed during the fetal, childhood and/or pubertal stage, including unilateral condylar hyperactivity, functional disharmony of the masticatory muscles, dominance of one cerebral hemisphere, plagiocephaly, unilateral craniosynostosis, among others. The time of evolution prior to its detection contributes to the level of expression of the asymmetry. By means of a literature review, the proposal of a differential diagram and the presentation of a case report which includes facial analysis, cephalometric analysis, 3D tomographic reconstruction and findings of nuclear medicine, differential diagrams are suggested as well as a new classification of facial asymmetry. The differential diagnosis between asymmetry of the glenoid fossa and hemimandibular elongation is established, which requires a careful correlation of clinical findings and imaging tests, since both have similar clinical characteristics, but differ in their therapeutic approach.

Respiratory Research

Background: Idiopathic pulmonary fibrosis (IPF) is an age-related, progressive and lethal disease... more Background: Idiopathic pulmonary fibrosis (IPF) is an age-related, progressive and lethal disease, whose pathogenesis is associated with fibroblasts/myofibroblasts foci that produce excessive extracellular matrix accumulation in lung parenchyma. Hypoxia has been described as a determinant factor in its development and progression. However, the role of distinct members of this pathway is not completely described. Methods: By western blot, quantitative PCR, Immunohistochemistry and Immunocitochemistry were evaluated, the expression HIF alpha subunit isoforms 1, 2 & 3 as well, as their role in myofibroblast differentiation in lung tissue and fibroblast cell lines derived from IPF patients. Results: Hypoxia signaling pathway was found very active in lungs and fibroblasts from IPF patients, as demonstrated by the abundance of alpha subunits 1 and 2, which further correlated with the increased expression of myofibroblast marker αSMA. In contrast, HIF-3α showed reduced expression associated with its promoter hypermethylation. Conclusions: This study lends further support to the involvement of hypoxia in the pathogenesis of IPF, and poses HIF-3α expression as a potential negative regulator of these phenomena.

Oncotarget, Jan 30, 2018

Histone demethylase KDM4A is involved in H3K9me3 and H3K36me3 demethylation, which are epigenetic... more Histone demethylase KDM4A is involved in H3K9me3 and H3K36me3 demethylation, which are epigenetic modifications associated with gene silencing and RNA Polymerase II elongation, respectively. is abnormally expressed in cancer, affecting the expression of multiple targets, such as the gene. This enzyme localizes at the first intron of , and the dissociation of KDM4A increases gene expression. assays showed that KDM4A-mediated demethylation is enhanced in the presence of CTCF, suggesting that CTCF could increase its enzymatic activity however the specific mechanism by which and might be involved in the gene repression is poorly understood. Here, we show that CTCF and KDM4A form a protein complex, which is recruited into the first intron of . This is related to a decrease in H3K36me3/2 histone marks and is associated with its transcriptional downregulation. Depletion of or KDM4A by siRNA, triggered the reactivation of expression, suggesting that both proteins are involved in the negativ...

Molecular and Cellular Probes

Oncology Letters, 2016

Epidermal growth factor receptor (EGFR) is overexpressed in >60% of non-small cell lung cancer (N... more Epidermal growth factor receptor (EGFR) is overexpressed in >60% of non-small cell lung cancer (NSCLC) cases. In combination with radiotherapy or chemotherapy, first-line treatments with antibodies against EGFR, including cetuximab and necitumumab, have demonstrated benefits by increasing overall survival (OS), particularly in patients who overexpress EGFR. The present study evaluated the interobserver agreement among three senior pathologists, who were blinded to the clinical outcomes and assessed tumor samples from 85 patients with NSCLC using the H-score method. EGFR immunohistochemistry was performed using a qualitative immunohistochemical kit. The reported (mean ± standard deviation) H-scores from each pathologist were 111±102, 127±103 and 128.53±104.03. The patients with average H-scores ≥1, ≥100, ≥200 and between 250-300 were 85.9, 54.1, 28.2 and 12.9, respectively. Patients who had an average H-score >100 had a shorter OS time compared with those with lower scores. Furthermore, patients with EGFR mutations who were treated with EGFR-tyrosine kinase inhibitors (TKIs) and had an average H-score >100 had a longer OS time compared with those with an average H-score <100. The interobserver concordance for the total H-scores were 0.982, 0.980 and 0.988, and for a positive H-score ≥200, the interobserver concordance was 0.773, 0.710 and 0.675, respectively. The determination of EGFR expression by the H-score method is highly reproducible among pathologists and is a prognostic factor associated with a poor OS in all patients. Additionally, the results of the present study suggest that patients with EGFR mutations that are treated with EGFR-TKIs and present with a high H-score have a longer OS time.

Oncology Reports, 2015

Hypoxic tumor cells are known to be more resistant to conventional chemotherapy and radiation tha... more Hypoxic tumor cells are known to be more resistant to conventional chemotherapy and radiation than normoxic cells. However, the effects of 2-methoxyestradiol (2-ME), an anti-angiogenic, antiproliferative and pro-apoptotic drug, on hypoxic lung cancer cells are unknown. The aim of the present study was to compare the effects of 2-ME on cell growth, apoptosis, hypoxia-inducible factor 1α (HIF-1α) and HIF-2α gene and protein expression in A549 cells under normoxic and hypoxic conditions. To establish the optimal 2-ME concentration with which to carry out the apoptosis assay and to examine mRNA and protein expression of HIFs, cell growth analysis was carried out through N-hexa-methylpararosaniline staining assays in A549 cell cultures treated with one of five different 2-ME concentrations at different times under normoxic or hypoxic growth conditions. The 2-ME concentration of 10 mM at 72 h was selected to perform all further experiments. Apoptotic cells were analyzed by flow cytometry. Western blotting was used to determine HIF-1α and HIF-2α protein expression in total cell extracts. Cellular localization of HIF-1α and HIF-2α was assessed by immunocytochemistry. HIF-1α and HIF-2α gene expression was determined by real-time PCR. A significant increase in the percentage of apoptosis was observed when cells were treated with 2-ME under a normoxic but not under hypoxic conditions (p=0.006). HIF-1α and HIF-2α protein expression levels were significantly decreased in cells cultured under hypoxic conditions and treated with 2-ME (p<0.001). Furthermore, 2-ME decreased the HIF-1α and HIF-2α nuclear staining in cells cultured under hypoxia. The HIF-1α and HIF-2α mRNA levels were significantly lower when cells were exposed to 2-ME under normoxia and hypoxia. Our results suggest that 2-ME could have beneficial results when used with conventional chemotherapy in an attempt to lower the invasive and metastatic processes during cancer development due to its effects on the gene expression and protein synthesis of HIFs.

Journal of Gastrointestinal Cancer, 2011

Characterize the frequency, density, and distribution of Aberrant Crypt Foci (ACF), its histologi... more Characterize the frequency, density, and distribution of Aberrant Crypt Foci (ACF), its histological features and determine the frequency of loss of expression of DNA mismatch repair (MMR) proteins of subjects with Hereditary Non-Polyposic Colorectal Cancer (HNPCC) and sporadic Colon Rectal Cancer (CRC). Methods: Patients with HNPCC, first-degree relatives of subjects with HNPCC, sporadic CRC and average risk subjects of sporadic CRC, were included prospectively. Total colonoscopy with chromoendoscopy using methylene blue 0.5% and magnification in the right colon (cecum and 20 cm of the ascending colon) and in the left colon (rectum) was performed; loss of expression of MLH1 and MSH2 was evaluated by Immunohistochemistry (IHC) in confirmed ACF. Results: Fifty two subjects were included. Thirty-eight of the 119 ACF detected by endoscopy were biopsied. In 14 of the 38 specimens (36.8%), ACF were confirmed by histology (Cohen's kappa, 0.44). In subjects with HNPCC ACF were identified more frequently in the right segment of the colon than the left (73.1 vs. 26%); in contrast, ACF predominated in the left segment of the colon (89.3 vs. 10.6%), in subjects with sporadic CRC. There was a loss of MLH1 expression in ACF in subjects with HNPCC. Conclusions: In HNPCC, we found a greater density of ACF in the right colon, and in sporadic CRC, greater density in the left. ACF presents loss in the expression of DNA *Revised manuscript including track changes Click here to download Revised manuscript including track changes: manuscript red.docx MMR Protein and can be used as an early marker in patients with a risk of HNPCC in whom carcinogenesis appears to be accelerated.

Revista Mexicana de Ortodoncia

Facial asymmetry is one of the main findings during clinical practice with a prevalence between 2... more Facial asymmetry is one of the main findings during clinical practice with a prevalence between 21-85%; this causes both functional and aesthetic problems, and is manifested by an inconsistency in size, shape, or position of craniofacial structures on both sides of the mid-sagittal plane. Its etiology is attributed to hereditary and/ or environmental factors that may be expressed during the fetal, childhood and/or pubertal stage, including unilateral condylar hyperactivity, functional disharmony of the masticatory muscles, dominance of one cerebral hemisphere, plagiocephaly, unilateral craniosynostosis, among others. The time of evolution prior to its detection contributes to the level of expression of the asymmetry. By means of a literature review, the proposal of a differential diagram and the presentation of a case report which includes facial analysis, cephalometric analysis, 3D tomographic reconstruction and findings of nuclear medicine, differential diagrams are suggested as well as a new classification of facial asymmetry. The differential diagnosis between asymmetry of the glenoid fossa and hemimandibular elongation is established, which requires a careful correlation of clinical findings and imaging tests, since both have similar clinical characteristics, but differ in their therapeutic approach.

Pathology and Oncology Research, 2021

Background: Programmed cell death-ligand 1 (PD-L1) protein expression is one of the most extensiv... more Background: Programmed cell death-ligand 1 (PD-L1) protein expression is one of the most extensively studied biomarkers in patients with non-small cell lung cancer (NSCLC). However, there is scarce information regarding its association with distinct adenocarcinoma subtypes. This study evaluated the frequency of PD-L1 expression according to the IASLC/ATS/ERS classification and other relevant histological and clinical features. Patients and Methods: PD-L1 expression was assessed by immunohistochemistry (IHC). According to its positivity in tumor cells membrane, we stratified patients in three different tumor proportions score (TPS) cut-off points: a) <1% (negative), b) between 1 and 49%, and c) ≥50%; afterward, we analyzed the association among PD-L1 expression and lung adenocarcinoma (LADC) predominant subtypes, as well as other clinical features. As an exploratory outcome we evaluated if a PD-L1 TPS score ≥15% was useful as a biomarker for determining survival. Results: A total ...

Cancers

In triple-negative breast cancer (TNBC), only 30% of patients treated with neoadjuvant chemothera... more In triple-negative breast cancer (TNBC), only 30% of patients treated with neoadjuvant chemotherapy achieve a pathological complete response after treatment and more than 90% die due to metastasis formation. The diverse clinical responses and metastatic developments are attributed to extensive intrapatient genetic heterogeneity and tumor evolution acting on this neoplasm. In this work, we aimed to evaluate genomic alterations and tumor evolution in TNBC patients with aggressive disease. We sequenced the whole exome of 16 lesions from four patients who did not respond to therapy, and took several follow-up samples, including samples from tumors before and after treatment, as well as from the lymph nodes and skin metastases. We found substantial intrapatient genetic heterogeneity, with a variable tumor mutational composition. Early truncal events were MCL1 amplifications. Metastatic lesions had deletions in RB1 and PTEN, along with TERT, AKT2, and CCNE1 amplifications. Mutational sign...

Revista de investigación clínica; organo del Hospital de Enfermedades de la Nutrición

High-grade intraepithelial neoplasia (HGPIN) is the only lesion regarded as precursor of prostati... more High-grade intraepithelial neoplasia (HGPIN) is the only lesion regarded as precursor of prostatic carcinoma, though its frequency is unknown in many countries. Here we studied the frequency of HGPIN in a population with high grade frequency of prostatic carcinoma. A total of 486 cases of sextant prostatic biopsies performed from January 2001 to January 2006 were reviewed. These included 280 biopsies from patients belonging to an urban population, with medium or high socioeconomic status, from two hospitals in Mexico City. For comparison, 206 cases from the Regional Hospital of Tabasco located in the tropical zone of the country were included. This hospital receives patients from a rural population with low income and socioeconomic status. Of the total 486 cases, 162 (33.33%) cases were diagnosed as prostatic carcinoma and 319 (65.64%) as benign conditions. Only in five (1.03%) biopsies was HGPIN found. Three of these patients were from Mexico City, and two from the Regional Hospita...

Genes

Triple-negative breast cancer (TNBC) presents a marked diversity at the molecular level, which pr... more Triple-negative breast cancer (TNBC) presents a marked diversity at the molecular level, which promotes a clinical heterogeneity that further complicates treatment. We performed a detailed whole exome sequencing profile of 29 Mexican patients with long follow-up TNBC to identify genomic alterations associated with overall survival (OS), disease-free survival (DFS), and pathologic complete response (PCR), with the aim to define their role as molecular predictive factors of treatment response and prognosis. We detected 31 driver genes with pathogenic mutations in TP53 (53%), BRCA1/2 (27%), CDKN1B (9%), PIK3CA (9%), and PTEN (9%), and 16 operative mutational signatures. Moreover, tumors with mutations in BRCA1/2 showed a trend of sensitivity to platinum salts. We found an association between deficiency in DNA repair and surveillance genes and DFS. Across all analyzed tumors we consistently found a heterogeneous molecular complexity in terms of allelic composition and operative mutation...

The Journal of Molecular Diagnostics

Breast cancer is one of the leading causes of mortality in women worldwide, neoadjuvant chemother... more Breast cancer is one of the leading causes of mortality in women worldwide, neoadjuvant chemotherapy has emerged as an option for the management of locally advanced breast cancer. Extensive efforts have been made to identify new molecular markers to predict the response to neoadjuvant chemotherapy. Transcripts that do not encode proteins, termed lncRNAs, have been shown to display abnormal expression profiles in different types of cancer but their role as biomarkers in response to neoadjuvant chemotherapy has not been extensively studied. Herein, lncRNA expression was profiled using RNA-Seq in biopsies from patients who subsequently showed either response or no response to treatment. The GATA3-AS1 transcript was overexpressed in the nonresponder group and was the most stable feature when performing selection in multiple random forest models. GATA3-AS1 was experimentally validated by RT-qPCR in an extended group of 68 patients. Expression analysis confirmed that GATA3-AS1 is overexpressed primarily in patients who were nonresponsive to neoadjuvant chemotherapy with a sensitivity of 92.9%, specificity of 75.0% and an AUC of ∼0.90 as measured by ROC curve analysis. The statistical model based on Luminal B-like patients adjusted by menopausal status and phenotype (OR= 37.49; 95% CI= 6.74-208.42 P= 0.001), GATA3-AS1 was established as an independent predictor of response. Thus, lncRNA GATA3-AS1 is proposed as a potential predictive biomarker of nonresponse to neoadjuvant chemotherapy.

Turkish Journal of Surgery

Objective: Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors that express type 3 tyr... more Objective: Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors that express type 3 tyrosine kinase receptors and are thought to develop from the neoplastic transformation of the interstitial Cajal cells. The present study was performed to morphologically and immunohistologically evaluate GISTs, to compare their qualities using a GIST risk categorization system, and to identify the diagnostic and prognostic parameters of GISTs. Material and Methods: A total of 27 patients with GISTs underwent treatment and were followed up at the Gaziosmanpaşa Taksim Training and Research Hospital. Descriptive statistics was used to calculate the mean and median values. Survival analysis was performed by the Kaplan-Meier method. The analyses were performed using the SPSS version 22.0 software. Results: The mean follow-up time was 3.5 (5 months to 13 years) years. The mean age was 60.4 (29-82) years. The tumors were localized in the stomach (62.9%), extraintestinal areas (14.8%), intestine (7.4%), esophagus (7.4%), and rectum (7.4%). Twenty-four patients were classified according to the Fletcher system. Of these patients, 7 (25.9%) were classified as very low risk, 8 (29.6%) as low risk, 7 (25.9%) as intermediate risk, and 2 (7.4%) as high risk. Twenty-four patients underwent surgery. Of the 3 patients who did not undergo surgery, 1 had metastatic disease at the time of diagnosis, and 2 had mini-or micro-GISTs in the stomach. On endoscopic surveillance, all tumors remained stable. Three out of the 27 patients were lost to follow-up. Two patients developed recurrence, and 1 patient died of GIST. Conclusion: We analyzed the clinical and pathological characteristics of GIST. The most common site of tumor origin was the stomach. The size, mitotic index, and Ki-67 values were to be found high in intermediate-and high-risk groups and metastatic diseases.

Revista Mexicana de Ortodoncia

Facial asymmetry is one of the main findings during clinical practice with a prevalence between 2... more Facial asymmetry is one of the main findings during clinical practice with a prevalence between 21-85%; this causes both functional and aesthetic problems, and is manifested by an inconsistency in size, shape, or position of craniofacial structures on both sides of the mid-sagittal plane. Its etiology is attributed to hereditary and/ or environmental factors that may be expressed during the fetal, childhood and/or pubertal stage, including unilateral condylar hyperactivity, functional disharmony of the masticatory muscles, dominance of one cerebral hemisphere, plagiocephaly, unilateral craniosynostosis, among others. The time of evolution prior to its detection contributes to the level of expression of the asymmetry. By means of a literature review, the proposal of a differential diagram and the presentation of a case report which includes facial analysis, cephalometric analysis, 3D tomographic reconstruction and findings of nuclear medicine, differential diagrams are suggested as well as a new classification of facial asymmetry. The differential diagnosis between asymmetry of the glenoid fossa and hemimandibular elongation is established, which requires a careful correlation of clinical findings and imaging tests, since both have similar clinical characteristics, but differ in their therapeutic approach.

Respiratory Research

Background: Idiopathic pulmonary fibrosis (IPF) is an age-related, progressive and lethal disease... more Background: Idiopathic pulmonary fibrosis (IPF) is an age-related, progressive and lethal disease, whose pathogenesis is associated with fibroblasts/myofibroblasts foci that produce excessive extracellular matrix accumulation in lung parenchyma. Hypoxia has been described as a determinant factor in its development and progression. However, the role of distinct members of this pathway is not completely described. Methods: By western blot, quantitative PCR, Immunohistochemistry and Immunocitochemistry were evaluated, the expression HIF alpha subunit isoforms 1, 2 & 3 as well, as their role in myofibroblast differentiation in lung tissue and fibroblast cell lines derived from IPF patients. Results: Hypoxia signaling pathway was found very active in lungs and fibroblasts from IPF patients, as demonstrated by the abundance of alpha subunits 1 and 2, which further correlated with the increased expression of myofibroblast marker αSMA. In contrast, HIF-3α showed reduced expression associated with its promoter hypermethylation. Conclusions: This study lends further support to the involvement of hypoxia in the pathogenesis of IPF, and poses HIF-3α expression as a potential negative regulator of these phenomena.

Oncotarget, Jan 30, 2018

Histone demethylase KDM4A is involved in H3K9me3 and H3K36me3 demethylation, which are epigenetic... more Histone demethylase KDM4A is involved in H3K9me3 and H3K36me3 demethylation, which are epigenetic modifications associated with gene silencing and RNA Polymerase II elongation, respectively. is abnormally expressed in cancer, affecting the expression of multiple targets, such as the gene. This enzyme localizes at the first intron of , and the dissociation of KDM4A increases gene expression. assays showed that KDM4A-mediated demethylation is enhanced in the presence of CTCF, suggesting that CTCF could increase its enzymatic activity however the specific mechanism by which and might be involved in the gene repression is poorly understood. Here, we show that CTCF and KDM4A form a protein complex, which is recruited into the first intron of . This is related to a decrease in H3K36me3/2 histone marks and is associated with its transcriptional downregulation. Depletion of or KDM4A by siRNA, triggered the reactivation of expression, suggesting that both proteins are involved in the negativ...

Molecular and Cellular Probes

Oncology Letters, 2016

Epidermal growth factor receptor (EGFR) is overexpressed in >60% of non-small cell lung cancer (N... more Epidermal growth factor receptor (EGFR) is overexpressed in >60% of non-small cell lung cancer (NSCLC) cases. In combination with radiotherapy or chemotherapy, first-line treatments with antibodies against EGFR, including cetuximab and necitumumab, have demonstrated benefits by increasing overall survival (OS), particularly in patients who overexpress EGFR. The present study evaluated the interobserver agreement among three senior pathologists, who were blinded to the clinical outcomes and assessed tumor samples from 85 patients with NSCLC using the H-score method. EGFR immunohistochemistry was performed using a qualitative immunohistochemical kit. The reported (mean ± standard deviation) H-scores from each pathologist were 111±102, 127±103 and 128.53±104.03. The patients with average H-scores ≥1, ≥100, ≥200 and between 250-300 were 85.9, 54.1, 28.2 and 12.9, respectively. Patients who had an average H-score >100 had a shorter OS time compared with those with lower scores. Furthermore, patients with EGFR mutations who were treated with EGFR-tyrosine kinase inhibitors (TKIs) and had an average H-score >100 had a longer OS time compared with those with an average H-score <100. The interobserver concordance for the total H-scores were 0.982, 0.980 and 0.988, and for a positive H-score ≥200, the interobserver concordance was 0.773, 0.710 and 0.675, respectively. The determination of EGFR expression by the H-score method is highly reproducible among pathologists and is a prognostic factor associated with a poor OS in all patients. Additionally, the results of the present study suggest that patients with EGFR mutations that are treated with EGFR-TKIs and present with a high H-score have a longer OS time.

Oncology Reports, 2015

Hypoxic tumor cells are known to be more resistant to conventional chemotherapy and radiation tha... more Hypoxic tumor cells are known to be more resistant to conventional chemotherapy and radiation than normoxic cells. However, the effects of 2-methoxyestradiol (2-ME), an anti-angiogenic, antiproliferative and pro-apoptotic drug, on hypoxic lung cancer cells are unknown. The aim of the present study was to compare the effects of 2-ME on cell growth, apoptosis, hypoxia-inducible factor 1α (HIF-1α) and HIF-2α gene and protein expression in A549 cells under normoxic and hypoxic conditions. To establish the optimal 2-ME concentration with which to carry out the apoptosis assay and to examine mRNA and protein expression of HIFs, cell growth analysis was carried out through N-hexa-methylpararosaniline staining assays in A549 cell cultures treated with one of five different 2-ME concentrations at different times under normoxic or hypoxic growth conditions. The 2-ME concentration of 10 mM at 72 h was selected to perform all further experiments. Apoptotic cells were analyzed by flow cytometry. Western blotting was used to determine HIF-1α and HIF-2α protein expression in total cell extracts. Cellular localization of HIF-1α and HIF-2α was assessed by immunocytochemistry. HIF-1α and HIF-2α gene expression was determined by real-time PCR. A significant increase in the percentage of apoptosis was observed when cells were treated with 2-ME under a normoxic but not under hypoxic conditions (p=0.006). HIF-1α and HIF-2α protein expression levels were significantly decreased in cells cultured under hypoxic conditions and treated with 2-ME (p<0.001). Furthermore, 2-ME decreased the HIF-1α and HIF-2α nuclear staining in cells cultured under hypoxia. The HIF-1α and HIF-2α mRNA levels were significantly lower when cells were exposed to 2-ME under normoxia and hypoxia. Our results suggest that 2-ME could have beneficial results when used with conventional chemotherapy in an attempt to lower the invasive and metastatic processes during cancer development due to its effects on the gene expression and protein synthesis of HIFs.

Journal of Gastrointestinal Cancer, 2011

Characterize the frequency, density, and distribution of Aberrant Crypt Foci (ACF), its histologi... more Characterize the frequency, density, and distribution of Aberrant Crypt Foci (ACF), its histological features and determine the frequency of loss of expression of DNA mismatch repair (MMR) proteins of subjects with Hereditary Non-Polyposic Colorectal Cancer (HNPCC) and sporadic Colon Rectal Cancer (CRC). Methods: Patients with HNPCC, first-degree relatives of subjects with HNPCC, sporadic CRC and average risk subjects of sporadic CRC, were included prospectively. Total colonoscopy with chromoendoscopy using methylene blue 0.5% and magnification in the right colon (cecum and 20 cm of the ascending colon) and in the left colon (rectum) was performed; loss of expression of MLH1 and MSH2 was evaluated by Immunohistochemistry (IHC) in confirmed ACF. Results: Fifty two subjects were included. Thirty-eight of the 119 ACF detected by endoscopy were biopsied. In 14 of the 38 specimens (36.8%), ACF were confirmed by histology (Cohen's kappa, 0.44). In subjects with HNPCC ACF were identified more frequently in the right segment of the colon than the left (73.1 vs. 26%); in contrast, ACF predominated in the left segment of the colon (89.3 vs. 10.6%), in subjects with sporadic CRC. There was a loss of MLH1 expression in ACF in subjects with HNPCC. Conclusions: In HNPCC, we found a greater density of ACF in the right colon, and in sporadic CRC, greater density in the left. ACF presents loss in the expression of DNA *Revised manuscript including track changes Click here to download Revised manuscript including track changes: manuscript red.docx MMR Protein and can be used as an early marker in patients with a risk of HNPCC in whom carcinogenesis appears to be accelerated.

Revista Mexicana de Ortodoncia

Facial asymmetry is one of the main findings during clinical practice with a prevalence between 2... more Facial asymmetry is one of the main findings during clinical practice with a prevalence between 21-85%; this causes both functional and aesthetic problems, and is manifested by an inconsistency in size, shape, or position of craniofacial structures on both sides of the mid-sagittal plane. Its etiology is attributed to hereditary and/ or environmental factors that may be expressed during the fetal, childhood and/or pubertal stage, including unilateral condylar hyperactivity, functional disharmony of the masticatory muscles, dominance of one cerebral hemisphere, plagiocephaly, unilateral craniosynostosis, among others. The time of evolution prior to its detection contributes to the level of expression of the asymmetry. By means of a literature review, the proposal of a differential diagram and the presentation of a case report which includes facial analysis, cephalometric analysis, 3D tomographic reconstruction and findings of nuclear medicine, differential diagrams are suggested as well as a new classification of facial asymmetry. The differential diagnosis between asymmetry of the glenoid fossa and hemimandibular elongation is established, which requires a careful correlation of clinical findings and imaging tests, since both have similar clinical characteristics, but differ in their therapeutic approach.