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1.
Biomedicines ; 11(9)2023 Sep 08.
Article in English | MEDLINE | ID: mdl-37760937

ABSTRACT

BACKGROUND: Determining the infiltration of carcinomas is essential for the proper follow-up and treatment of cancer patients. However, it continues to be a diagnostic challenge for pathologists in multiple types of tumors. In previous studies (carried out in surgical specimens), the protein COL11A1 has been postulated as an infiltration marker mainly expressed in the extracellular matrix (ECM). We hypothesized that a differential expression of COL11A1 may exist in the peritumoral stroma of tumors that have acquired infiltrating properties and that it may be detected in the small biopsies usually available in normal clinical practice. MATERIAL AND METHODS: In our study, we performed immunohistochemical staining in more than 350 invasive and noninvasive small samples obtained via core needle biopsy (CNB), colonoscopy, or transurethral resection of bladder tumor (TURBT) of breast, colorectal, bladder, and ovarian cancer. RESULTS: Our results revealed that COL11A1 immunostaining had a sensitivity to classify the samples into infiltrative vs. noninfiltrative tumors of 94% (breast), 97% (colorectal), >90% (bladder), and 74% (ovarian); and a specificity of 97% (breast), 100% (colorectal), and >90% (bladder). In ovarian cancer, the negative predictive value (0.59) did not present improvement over the usual histopathological markers. In all samples tested, the cumulative sensitivity was 86% and the specificity 96% (p < 0.0001). CONCLUSIONS: COL11A1-positive immunostaining in small biopsies of breast, colon, bladder and ovarian cancer is an accurate predictive marker of tumor infiltration that can be easily implemented in daily clinical practice.

2.
Front Med (Lausanne) ; 10: 1151843, 2023.
Article in English | MEDLINE | ID: mdl-37484846

ABSTRACT

Introduction: Whole-body autopsies may be crucial to understand coronavirus disease 2019 (COVID-19) pathophysiology. We aimed to analyze pathological findings in a large series of full-body autopsies, with a special focus on superinfections. Methods: This was a prospective multicenter study that included 70 COVID-19 autopsies performed between April 2020 and February 2021. Epidemiological, clinical and pathological information was collected using a standardized case report form. Results: Median (IQR) age was 70 (range 63.75-74.25) years and 76% of cases were males. Most patients (90%,) had at least one comorbidity prior to COVID-19 diagnosis, with vascular risk factors being the most frequent. Infectious complications were developed by 65.71% of the patients during their follow-up. Mechanical ventilation was required in most patients (75.71%) and was mainly invasive. In multivariate analyses, length of hospital stay and invasive mechanical ventilation were significantly associated with infections (p = 0.036 and p = 0.013, respectively). Necropsy findings revealed diffuse alveolar damage in the lungs, left ventricular hypertrophy in the heart, liver steatosis and pre-infection arteriosclerosis in the heart and kidneys. Conclusion: Our study confirms the main necropsy histopathological findings attributed to COVID-19 in a large patient series, while underlining the importance of both comorbid conditions and superinfections in the pathology.

3.
Rev. esp. patol ; 56(2): 97-112, Abr-Jun 2023. tab, ilus
Article in Spanish | IBECS | ID: ibc-219164

ABSTRACT

El carcinoma de pulmón de no célula pequeña (CPNCP) presenta el mayor número de dianas terapéuticas identificadas, algunas de ellas con utilidad terapéutica. En la actualidad se considera imprescindible en estos pacientes determinar las mutaciones de EGFR, BRAF, KRAS y MET, las traslocaciones de ALK, ROS1, NTRK y RET y la expresión de PD-L1. El uso de la secuenciación masiva (next-generation sequencing [NGS]) facilita el diagnóstico molecular de forma precisa y permite determinar otras mutaciones emergentes, como la mutación de HER2 y los biomarcadores predictivos de respuesta a inmunoterapia. En este consenso, un grupo de expertos en el diagnóstico y tratamiento del CPNCP seleccionado por la Sociedad Española de Anatomía Patológica (SEAP) y la Sociedad Española de Oncología Médica (SEOM) ha evaluado la información actualmente disponible y propone una serie de recomendaciones para optimizar la determinación y utilización en la práctica clínica diaria de los biomarcadores.(AU)


Non-small cell lung cancer (NSCLC) presents the greatest number of identified therapeutic targets, some of which have therapeutic utility. Currently, detecting EGFR, BRAF, KRAS and MET mutations, ALK, ROS1, NTRK and RET translocations, and PD-L1 expression in these patients is considered essential. The use of next-generation sequencing (NGS) facilitates precise molecular diagnosis and allows the detection of other emerging mutations, such as the HER2 mutation and predictive biomarkers for immunotherapy responses. In this consensus, a group of experts in the diagnosis and treatment of NSCLC selected by the Spanish Society of Pathology (SEAP) and the Spanish Society of Medical Oncology (SEOM) have evaluated currently available information and propose a series of recommendations to optimize the detection and use of biomarkers in daily clinical practice.(AU)


Subject(s)
Humans , Carcinoma, Non-Small-Cell Lung , Biomarkers , Consensus , Medical Oncology , Pathology , Spain
4.
Clin. transl. oncol. (Print) ; 25(5): 1252-1267, mayo 2023. ilus
Article in English | IBECS | ID: ibc-219510

ABSTRACT

Non-small cell lung cancer (NSCLC) presents the greatest number of identified therapeutic targets, some of which have therapeutic utility. Currently, detecting EGFR, BRAF, KRAS and MET mutations, ALK, ROS1, NTRK and RET translocations, and PD-L1 expression in these patients is considered essential. The use of next-generation sequencing facilitates precise molecular diagnosis and allows the detection of other emerging mutations, such as the HER2 mutation and predictive biomarkers for immunotherapy responses. In this consensus, a group of experts in the diagnosis and treatment of NSCLC selected by the Spanish Society of Pathology and the Spanish Society of Medical Oncology have evaluated currently available information and propose a series of recommendations to optimize the detection and use of biomarkers in daily clinical practice (AU)


Subject(s)
Humans , Biomarkers, Tumor/genetics , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/therapy , Lung Neoplasms/genetics , Lung Neoplasms/therapy , Protein-Tyrosine Kinases/genetics , Proto-Oncogenes/genetics , Societies, Medical , Consensus , Spain
6.
Rev Esp Patol ; 56(2): 97-112, 2023.
Article in Spanish | MEDLINE | ID: mdl-37061248

ABSTRACT

Non-small cell lung cancer (NSCLC) presents the greatest number of identified therapeutic targets, some of which have therapeutic utility. Currently, detecting EGFR, BRAF, KRAS and MET mutations, ALK, ROS1, NTRK and RET translocations, and PD-L1 expression in these patients is considered essential. The use of next-generation sequencing (NGS) facilitates precise molecular diagnosis and allows the detection of other emerging mutations, such as the HER2 mutation and predictive biomarkers for immunotherapy responses. In this consensus, a group of experts in the diagnosis and treatment of NSCLC selected by the Spanish Society of Pathology (SEAP) and the Spanish Society of Medical Oncology (SEOM) have evaluated currently available information and propose a series of recommendations to optimize the detection and use of biomarkers in daily clinical practice.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/therapy , Lung Neoplasms/pathology , Protein-Tyrosine Kinases , Consensus , Biomarkers, Tumor/genetics , Proto-Oncogene Proteins/genetics , Medical Oncology
8.
Rev Esp Patol ; 56(1): 58-68, 2023.
Article in English | MEDLINE | ID: mdl-36599601

ABSTRACT

Non-small cell lung cancer (NSCLC) is one of the oncological entities with the greatest evolution in molecular diagnosis due to the large number of diagnostic biomarkers and new treatments approved by international regulatory agencies. An accurate, early diagnosis using the least amount of tissue is the goal for the establishing and developing precision medicine for these patients. Rapid on-site evaluation (ROSE) provides cytological samples of optimal quantity and quality for a complete diagnosis of NSCLC. The usefulness of cytological samples has been demonstrated, not only for massive parallel sequencing but also for the quantification of the expression of programmed death-ligand 1 (PD-L1) and tumour mutational burden (TMB). Pre-analytical, analytical, and post-analytical recommendations are made for the management and appropriate use of cytological samples in order to obtain all the information necessary for the diagnosis and treatment of patients with NSCLC according to current quality parameters.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Lung Neoplasms/diagnosis , Lung Neoplasms/therapy , Carcinoma, Non-Small-Cell Lung/diagnosis , Carcinoma, Non-Small-Cell Lung/therapy , Immunohistochemistry , Cytodiagnosis
9.
Rev. esp. patol ; 56(1): 58-68, Ene-Mar. 2023. tab, ilus
Article in English | IBECS | ID: ibc-214177

ABSTRACT

Non-small cell lung cancer (NSCLC) is one of the oncological entities with the greatest evolution in molecular diagnosis due to the large number of diagnostic biomarkers and new treatments approved by international regulatory agencies. An accurate, early diagnosis using the least amount of tissue is the goal for the establishing and developing precision medicine for these patients. Rapid on-site evaluation (ROSE) provides cytological samples of optimal quantity and quality for a complete diagnosis of NSCLC. The usefulness of cytological samples has been demonstrated, not only for massive parallel sequencing but also for the quantification of the expression of programmed death-ligand 1 (PD-L1) and tumour mutational burden (TMB).Pre-analytical, analytical, and post-analytical recommendations are made for the management and appropriate use of cytological samples in order to obtain all the information necessary for the diagnosis and treatment of patients with NSCLC according to current quality parameters.(AU)


El cáncer de pulmón de célula no pequeña es la patología oncológica que más está evolucionando con respecto al diagnóstico molecular por la ingente cantidad de biomarcadores diagnósticos y nuevos tratamientos aprobados por las agencias regulatorias internacionales. La incorporación de la valoración in situ (Rapid On Site Evaluation) de las muestras obtenidas por punción-aspiración con aguja fina permite la obtención de muestras citológicas en cantidad y calidad óptimas para acometer un diagnóstico completo del cáncer de pulmón de célula no pequeña. La citología ha demostrado su utilidad en la secuenciación masiva, la determinación de la expresión del ligando 1 de muerte programada (programmed death-ligand 1) y de la carga mutacional (tumour mutational burden).En este documento se establecen recomendaciones preanalíticas, analíticas y postanalíticas que permiten manejar y aprovechar adecuadamente la muestra citológica para obtener toda la información necesaria para el diagnóstico y tratamiento del paciente con cáncer de pulmón de célula no pequeña con los parámetros de calidad exigibles hoy en día.(AU)


Subject(s)
Humans , Male , Female , eHealth Strategies , Cell Biology , Lung Neoplasms/diagnosis , Lung Neoplasms/therapy , Biomarkers , Prognosis , Cytodiagnosis , Neoplasms , Pathology, Clinical , Pathology , Spain
10.
Clin Transl Oncol ; 25(5): 1252-1267, 2023 May.
Article in English | MEDLINE | ID: mdl-36571695

ABSTRACT

Non-small cell lung cancer (NSCLC) presents the greatest number of identified therapeutic targets, some of which have therapeutic utility. Currently, detecting EGFR, BRAF, KRAS and MET mutations, ALK, ROS1, NTRK and RET translocations, and PD-L1 expression in these patients is considered essential. The use of next-generation sequencing facilitates precise molecular diagnosis and allows the detection of other emerging mutations, such as the HER2 mutation and predictive biomarkers for immunotherapy responses. In this consensus, a group of experts in the diagnosis and treatment of NSCLC selected by the Spanish Society of Pathology and the Spanish Society of Medical Oncology have evaluated currently available information and propose a series of recommendations to optimize the detection and use of biomarkers in daily clinical practice.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/diagnosis , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/therapy , Lung Neoplasms/diagnosis , Lung Neoplasms/genetics , Lung Neoplasms/therapy , Protein-Tyrosine Kinases/genetics , Consensus , Biomarkers, Tumor/genetics , Proto-Oncogene Proteins/genetics , Medical Oncology , Mutation
11.
Br J Pharmacol ; 179(18): 4534-4548, 2022 09.
Article in English | MEDLINE | ID: mdl-35726496

ABSTRACT

BACKGROUND AND PURPOSE: Interstitial lung disease (ILD) is the main cause of mortality in systemic sclerosis (SSc), and current therapies available are of low efficacy or high toxicity. Thus, the identification of innovative less toxic and high efficacy therapeutic approaches to ILD treatment is an urgent need. The interaction of P-selectin glycoprotein ligand-1 (PSGL-1) with P-selectin initiates leukocyte extravasation and deletion of the corresponding gene (Selplg) induces a SSc-like syndrome with high incidence of ILD in aged mice. EXPERIMENTAL APPROACH: Aged PSGL-1 KO (Selplg-/- ) mice were used to assess the therapeutic effects of nanotherapy with everolimus, included in liposomes decorated with high MW hyaluronic acid (LipHA+Ev) and administered intratracheally to specifically target CD44-expressing lung cells. KEY RESULTS: PSGL-1 KO mice had increased numbers of CD45+ and CD45- cells, including alveolar and interstitial macrophages, eosinophils, granulocytes and NK cells, and myofibroblasts in bronchoalveolar lavage (BAL). CD45+ and CD45- cells expressing pro-inflammatory and pro-fibrotic cytokines were also increased. Lungs from PSGL-1 KO mice showed increased immune cell infiltration and apoptosis and exacerbated interstitial and peribronchial fibrosis. Targeted nanotherapy with LipHA+Ev decreased the myofibroblasts in BAL, cells producing proinflammatory and profibrotic cytokines, and the degree of lung inflammation at histology. LipHA+Ev treatment also decreased the severity of peribronchial and interstitial lung fibrosis, from moderate to mild levels. CONCLUSIONS AND IMPLICATIONS: In PSGL-1 KO mice, targeted nanotherapy with LipHA+Ev was an effective treatment for SSc-ILD, reducing the number of inflammatory and fibrotic cells in BAL and reducing inflammation and fibrosis in lungs.


Subject(s)
Lung Diseases, Interstitial , Pulmonary Fibrosis , Scleroderma, Systemic , Animals , Cytokines , Everolimus/pharmacology , Everolimus/therapeutic use , Fibrosis , Inflammation/pathology , Lung/pathology , Lung Diseases, Interstitial/drug therapy , Lung Diseases, Interstitial/etiology , Membrane Glycoproteins , Mice , Pulmonary Fibrosis/drug therapy , Pulmonary Fibrosis/genetics , Scleroderma, Systemic/pathology
12.
Clin Exp Rheumatol ; 40(3): 581-588, 2022 Mar.
Article in English | MEDLINE | ID: mdl-34665698

ABSTRACT

OBJECTIVES: Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE). Unfortunately, 10-20% of patients with LN develop end-stage renal disease (ESRD), and renal transplantation may be a therapeutic option. However, concerns about LN recurrence after transplant have been reported. We aimed to assess long-term post-transplant graft and patient survival in LN compared to patients with non-autoimmune nephropathy (polycystic kidney disease - PCKD). METHODS: We carried out a single-centre retrospective study of all patients who underwent renal transplantation due to LN in a referral unit between 1980 and 2018. This cohort was compared with a group of PCKD patients. The main outcome variables were graft and patient survival for up to 20 years, and the time-course of serum creatinine and proteinuria in the first 5 years after transplantation. Cumulative survival rates were estimated by the Kaplan-Meier method and compared using the log-rank test. RESULTS: We included 53 patients: LN group (n=21) and PCKD group (n=32). Baseline clinical characteristics were similar in both groups, except age at transplantation (39.8±11.3 years in the LN group and 46.6±5.0 years in the PCKD group; p=0.004). No significant differences were found regarding graft (p=0.59) or patient survival (p=0.087) at 20 years of follow-up. CONCLUSIONS: Despite concerns about LN recurrence after renal transplantation, this study shows that this procedure might be a safe alternative therapy for ESRD related to SLE and may provide long-term survival.


Subject(s)
Kidney Failure, Chronic , Kidney Transplantation , Lupus Erythematosus, Systemic , Lupus Nephritis , Humans , Kidney Failure, Chronic/etiology , Kidney Failure, Chronic/surgery , Kidney Transplantation/adverse effects , Lupus Erythematosus, Systemic/complications , Lupus Nephritis/complications , Lupus Nephritis/drug therapy , Lupus Nephritis/surgery , Retrospective Studies , Treatment Outcome , Universities
13.
Exp Clin Transplant ; 20(12): 1069-1075, 2022 12.
Article in English | MEDLINE | ID: mdl-36718005

ABSTRACT

OBJECTIVES: The number of kidney transplants obtained from controlled donations after circulatory death is increasing, with long-term outcomes similar to those obtained with donations after brain death. Extraction using normothermic regional perfusion can improve results with controlled donors after circulatory death; however, information on the histological impact and extraction procedure is scarce. MATERIALS AND METHODS: We retrospectively investigated all kidney transplants performed from October 2014 to December 2019, in which a follow-up kidney biopsy had been performed at 1-year follow-up, comparing controlled procedures with donors after circulatory death and normothermic regional perfusion versus donors after brain death. Interstitial fibrosis/tubular atrophy was assessed by adding the values of interstitial fibrosis and tubular atrophy, according to the Banff classification of renal allograft pathology. RESULTS: When we compared histological data from 66 transplants with donations after brain death versus 24 transplants with donations after circulatory death and normothermic regional perfusion, no differences were found in the degree of fibrosis in the 1-year follow-up biopsy (1.7 ± 1.3 vs 1.7 ± 1.1; P = .971) or in the ratio of patients with increased fibrosis calculated as interstitial fibrosis/tubular atrophy >2 (18% vs 13%; P = .522). In our multivariate analysis, which included acute rejection, expanded criteria donation, and the type of donation, no variable was independently related to an increased risk of interstitial fibrosis/tubular atrophy >2. CONCLUSIONS: The outcomes of kidney grafts procured in our center using controlled procedures with donors after circulatory death and normothermic regional perfusion were indistinguishable from those obtained from donors after brain death, showing the same degree of fibrosis in the 1-year posttransplant surveillance biopsy. Our data support the conclusion that normothermic regional perfusion should be the method of choice for extraction in donors after circulatory death.


Subject(s)
Kidney Transplantation , Tissue and Organ Procurement , Humans , Kidney Transplantation/adverse effects , Kidney Transplantation/methods , Brain Death , Retrospective Studies , Graft Survival , Organ Preservation/adverse effects , Organ Preservation/methods , Perfusion/adverse effects , Perfusion/methods , Tissue Donors , Fibrosis , Biopsy , Atrophy/etiology , Death
14.
Front Cell Infect Microbiol ; 11: 633162, 2021.
Article in English | MEDLINE | ID: mdl-34631594

ABSTRACT

Context: It has been more than 10 years since the human papillomavirus (HPV) vaccination program was initiated in most advanced countries. Thus, it seems necessary to change the uterine cervical cancer screening strategy. Molecular-based tests are considered essential in this scenario. Objective: We aimed to review the distribution of the HPV genotypes after the introduction of the vaccination program with Cervarix® and Gardasil 4® in two autonomous communities in Spain, looking for possible changes in distribution and the occurrence of a herd effect. Design: A cross-sectional study was performed in 45,362 samples that were processed in the Cantabria and Aragon communities during the period from 2002 to 2016. We compared the genotype distribution before and after the vaccination program was initiated. Results: Genotypes HPV6 and HPV11 have decreased significantly after the introduction of the vaccine. HPV16 has had a decrease, but not a significant one in the statistical analysis. However, HPV31, HPV52, and HPV45 have increased in percentage. A replacement phenomenon with other genotypes not included in the vaccine has been observed in our population. Conclusions: Continued surveillance is needed to provide further indication of any changes over time in the genotypes in circulation. This will be facilitated by monitoring the genotyping results from the new model of cervical screening using primary HPV DNA testing.


Subject(s)
Papillomavirus Infections , Papillomavirus Vaccines , Uterine Cervical Neoplasms , Cross-Sectional Studies , Early Detection of Cancer , Female , Genotype , Human papillomavirus 16 , Humans , Papillomavirus Infections/prevention & control , Prevalence , Spain , Uterine Cervical Neoplasms/prevention & control , Vaccination
15.
Rom J Morphol Embryol ; 62(1): 309-312, 2021.
Article in English | MEDLINE | ID: mdl-34609437

ABSTRACT

INTRODUCTION: Mammary analogue secretory carcinoma (MASC) is a recent discovered entity of salivary glands tumors, reported for first time in 2010. The presence of a translocation encodes the ETS variant transcription factor 6-neurotrophic tyrosine receptor kinase (ETV6-NTRK3) gene fusion differences MASC from other tumors. CASE PRESENTATION: A 68-year-old male showed a non-painful right parotid enlargement, came from dermatology service, and followed by some facial squamous cell carcinomas. A computed tomography (CT) scan showed a 1.7×1.6 cm right parotid enlargement in superficial lobe. The patient underwent a right superficial parotidectomy. The final pathology confirmed the presence of ETV6-NTRK3-positive MASC. Complete right deep parotidectomy and functional cervical emptying were performed. DISCUSSIONS AND CONCLUSIONS: It is necessary to establish an appropriated differential diagnosis between salivary gland tumors. MASC is a low-grade malignancy cancer that sometimes can evolve to a high-grade tumor that might produce local and distance dissemination. Most times, these tumors are only treated by surgical resection and evaluating by a multidisciplinary team the need of more treatments. In our case, the patient showed a primary parotid tumor, removed surgically with free edges, and being identified as MASC. We decided to underwent neck dissection and discovered a second MASC focus on cervical salivary gland; however, there was no nodal dissemination. The patient remains disease-free after 14 months from last surgery. It is important to keep studying genetic therapy targets to ETV6-NTRK3 to obtain a new therapy line to treat those cases that require.


Subject(s)
Mammary Analogue Secretory Carcinoma , Salivary Gland Neoplasms , Aged , Biomarkers, Tumor , Humans , Male , Mammary Analogue Secretory Carcinoma/genetics , Oncogene Proteins, Fusion/genetics , Salivary Gland Neoplasms/genetics , Translocation, Genetic
16.
Rheumatol Int ; 41(6): 1161-1167, 2021 Jun.
Article in English | MEDLINE | ID: mdl-33834281

ABSTRACT

BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) is a recently recognized fibro-inflammatory pathology that has been reported to affect principally the retroperitoneum, hepatobiliary system, salivary glands, orbital structures or lymph nodes. However, IgG4-RD with laryngeal involvement is a very rare entity. Our aims were to describe a case of subglottic stenosis as first and only manifestation of IgG4-RD and review the literature. A patient with IgG4-RD affecting the larynx that presented as subglottic stenosis is described. A MEDLINE database search of IgG4-RD cases with laryngopharyngeal manifestations was also conducted. A 30-year-old Caucasian woman was referred to a tertiary care hospital for dyspnea on exertion, which had been increasing for the last 4 months. Medical and surgical procedures revealed a subglottic stenosis, with a histological finding of IgG4 positive plasma cell infiltration. There was no evidence of other organ involvement. She was successfully treated with oral glucocorticoids and rituximab infusions. Glucocorticoids were rapidly tapered and the rituximab regimen was optimized, with no evidence of relapses. In the literature review, we found a total of 12 reported cases with laryngopharyngeal involvement, two of them with subglottic stenosis. IgG4-RD of the larynx is rare but should be considered after excluding more common disorders.


Subject(s)
Immunoglobulin G4-Related Disease/diagnosis , Laryngeal Diseases/diagnosis , Adult , Aged , Constriction, Pathologic/etiology , Female , Humans , Immunoglobulin G4-Related Disease/drug therapy , Immunoglobulin G4-Related Disease/pathology , Immunologic Factors/administration & dosage , Laryngeal Diseases/drug therapy , Laryngeal Diseases/pathology , Male , Middle Aged , Rituximab/administration & dosage
17.
Oncogene ; 40(16): 2923-2935, 2021 04.
Article in English | MEDLINE | ID: mdl-33742126

ABSTRACT

The survival rate in lung cancer remains stubbornly low and there is an urgent need for the identification of new therapeutic targets. In the last decade, several members of the SWI/SNF chromatin remodeling complexes have been described altered in different tumor types. Nevertheless, the precise mechanisms of their impact on cancer progression, as well as the application of this knowledge to cancer patient management are largely unknown. In this study, we performed targeted sequencing of a cohort of lung cancer patients on genes involved in chromatin structure. In addition, we studied at the protein level the expression of these genes in cancer samples and performed functional experiments to identify the molecular mechanisms linking alterations of chromatin remodeling genes and tumor development. Remarkably, we found that 20% of lung cancer patients show ARID2 protein loss, partially explained by the presence of ARID2 mutations. In addition, we showed that ARID2 deficiency provokes profound chromatin structural changes altering cell transcriptional programs, which bolsters the proliferative and metastatic potential of the cells both in vitro and in vivo. Moreover, we demonstrated that ARID2 deficiency impairs DNA repair, enhancing the sensitivity of the cells to DNA-damaging agents. Our findings support that ARID2 is a bona fide tumor suppressor gene in lung cancer that may be exploited therapeutically.


Subject(s)
Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Transcription Factors/deficiency , A549 Cells , Animals , Cell Line, Tumor , Disease Progression , Female , High-Throughput Nucleotide Sequencing , Humans , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mice , Mice, Nude , Survival Rate , Transcription Factors/genetics , Transcription Factors/metabolism
18.
Nefrologia (Engl Ed) ; 41(3): 311-320, 2021.
Article in English, Spanish | MEDLINE | ID: mdl-33741175

ABSTRACT

BACKGROUND AND OBJECTIVE: About 25% of patients with IgA nephropathy (IgAN) progress to stage 5 chronic kidney disease (CKD) after years of evolution. Various tools have been developed in recent years designed to predict which of the patients will had poorer outcomes. The value of circulating galactosyl-deficient IgA1 (Gd-IgA1) has been related to a worse evolution of IgAN in several studies. There are also some publications that relate higher APRIL values with a worse evolution. Recently, a new method has been developed that allows measuring the value of circulating Gd-IgA1 in a simpler way than those previously available. The objective of this study is to analyze the influence of circulating Gd-IgA1, measured by this method, on the progression of IgAN. MATERIALS AND METHODS: Forty-nine patients with a diagnosis of IgAN demonstrated by renal biopsy were selected in our center, without having received prior immunosuppressive treatment, for whom frozen serum was available. The median follow-up was 4 years. Gd-IgA1 was measured by lectin-independent ELISA with the monoclonal antibody KM55 (IgA1 kit Cat. No. 30111694. IBL Int., Hamburg, Germany). Likewise, APRIL levels were also measured in these patients. RESULTS: 19 (38.8%) patients reached stage 5 CKD. The fourth quartile of circulating Gd-IgA1 was related to a higher cumulative risk of reaching stage 5 CKD in the Kaplan-Meier analysis (risk at the 5th year 39.4% vs. 24.3%, log rank p=0.019). The Gd-IgA1 value was related to an increased risk of CKD stage 5 (HR 1.147, 95% CI 1.035-1.270, p=0.009), regardless of glomerular filtration rate, proteinuria, the percentage of sclerosed glomeruli and the value of segmental sclerosis. We did not find significant differences in the APRIL values. CONCLUSIONS: The value of circulating Gd-IgA1 measured by the monoclonal antibody KM55 is related to a worse evolution of patients with IgAN independently of other variables, so it could be included in the study of patients to improve the prediction of the risk of disease progression.


Subject(s)
Antibodies, Monoclonal/blood , Glomerulonephritis, IGA/blood , Immunoglobulin A/immunology , Adult , Aged , Disease Progression , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Retrospective Studies , Risk Assessment , Time Factors
19.
Nefrologia (Engl Ed) ; 41(3): 311-320, 2021.
Article in English | MEDLINE | ID: mdl-36166247

ABSTRACT

BACKGROUND AND OBJECTIVE: About 25% of patients with IgA nephropathy (IgAN) progress to stage 5 chronic kidney disease (CKD) after years of evolution. Various tools have been developed in recent years designed to predict which of the patients will had poorer outcomes. The value of circulating galactosyl-deficient IgA1 (Gd-IgA1) has been related to a worse evolution of IgAN in several studies. There are also some publications that relate higher APRIL values with a worse evolution. Recently, a new method has been developed that allows measuring the value of circulating Gd-IgA1 in a simpler way than those previously available. The objective of this study is to analyze the influence of circulating Gd-IgA1, measured by this method, on the progression of IgAN. MATERIALS AND METHODS: Forty-nine patients with a diagnosis of IgAN demonstrated by renal biopsy were selected in our center, without having received prior immunosuppressive treatment, for whom frozen serum was available. The median follow-up was 4 years. Gd-IgA1 was measured by lectin-independent ELISA with the monoclonal antibody KM55 (IgA1 kit Cat. No. 30111694. IBL Int., Hamburg, Germany). Likewise, APRIL levels were also measured in these patients. RESULTS: 19 (38.8%) patients reached stage 5 CKD. The fourth quartile of circulating Gd-IgA1 was related to a higher cumulative risk of reaching stage 5 CKD in the Kaplan-Meier analysis (risk at the 5th year 39.4% vs. 24.3%, log rank p=0.019). The Gd-IgA1 value was related to an increased risk of CKD stage 5 (HR 1.147, 95% CI 1.035-1.270, p=0.009), regardless of glomerular filtration rate, proteinuria, the percentage of sclerosed glomeruli and the value of segmental sclerosis. We did not find significant differences in the APRIL values. CONCLUSIONS: The value of circulating Gd-IgA1 measured by the monoclonal antibody KM55 is related to a worse evolution of patients with IgAN independently of other variables, so it could be included in the study of patients to improve the prediction of the risk of disease progression.


Subject(s)
Glomerulonephritis, IGA , Renal Insufficiency, Chronic , Antibodies, Monoclonal , Galactose , Humans , Immunoglobulin A , Lectins
20.
PLoS One ; 15(4): e0232216, 2020.
Article in English | MEDLINE | ID: mdl-32348326

ABSTRACT

BACKGROUND: The knowledge of hereditary predisposition has changed our understanding of Pulmonary Arterial Hypertension. Genetic testing has been widely extended and the application of Pulmonary Arterial Hypertension specific gene panels has allowed its inclusion in the diagnostic workup and increase the diagnostic ratio compared to the traditional sequencing techniques. This is particularly important in the differential diagnosis between Pulmonary Arterial Hypertension and Pulmonary Venoocclusive Disease. METHODS: Since November 2011, genetic testing is offered to all patients with idiopathic, hereditable and associated forms of Pulmonary Arterial Hypertension or Pulmonary Venoocclusive Disease included in the Spanish Registry of Pulmonary Arterial Hypertension. Herein, we present the clinical phenotype and prognosis of all Pulmonary Arterial Hypertension patients with disease-associated variants in TBX4. RESULTS: Out of 579 adults and 45 children, we found in eight patients from seven families, disease-causing associated variants in TBX4. All adult patients had a moderate-severe reduction in diffusion capacity. However, we observed a wide spectrum of clinical presentations, including Pulmonary Venoocclusive Disease suspicion, interstitial lung disease, pulmonary vascular abnormalities and congenital heart disease. CONCLUSIONS: Genetic testing is now essential for a correct diagnosis work-up in Pulmonary Arterial Hypertension. TBX4-associated Pulmonary Arterial Hypertension has marked clinical heterogeneity. In this regard, a genetic study is extremely useful to obtain an accurate diagnosis and provide appropriate management.


Subject(s)
Familial Primary Pulmonary Hypertension/genetics , Genetic Variation , T-Box Domain Proteins/genetics , Adolescent , Adult , Child , Child, Preschool , Codon, Nonsense , Diagnosis, Differential , Familial Primary Pulmonary Hypertension/diagnosis , Familial Primary Pulmonary Hypertension/diagnostic imaging , Female , Gene Deletion , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Mutation, Missense , Pedigree , Phenotype , Polymorphism, Single Nucleotide , Prognosis , Pulmonary Veno-Occlusive Disease/diagnosis , Pulmonary Veno-Occlusive Disease/genetics
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