Publications by authors named "José Palacios"

219 Publications

Elevated Pediatric Chagas Disease Burden Complicated by Concomitant Intestinal Parasites and Malnutrition in El Salvador.

Trop Med Infect Dis 2021 May 7;6(2). Epub 2021 May 7.

Laboratory of Applied Entomology and Parasitology, School of Biology, University of San Carlos, Guatemala City, Guatemala.

The eradication of the vector from Central America was heralded as a victory for controlling transmission of , the parasite that causes Chagas disease. While public health officials believed this milestone achievement would effectively eliminate Chagas disease, case reports of acute vector transmission began amassing within a few years. This investigation employed a cross-sectional serosurvey of children either presenting with fever for clinical care or children living in homes with known triatomine presence in the state of Sonsonate, El Salvador. Over the 2018 calendar year, a 2.3% Chagas disease seroprevalence among children with hotspot clustering in Nahuizalco was identified. Positive serology was significantly associated with dogs in the home, older participant age, and a higher number of children in the home by multivariate regression. Concomitant intestinal parasitic infection was noted in a subset of studied children; 60% having at least one intestinal parasite and 15% having two or more concomitant infections. Concomitant parasitic infection was statistically associated with an overall higher parasitic load detected in stool by qPCR. Lastly, a four-fold higher burden of stunting was identified in the cohort compared to the national average, with four-fifths of mothers reporting severe food insecurity. This study highlights that polyparasitism is common, and a systems-based approach is warranted when treating Chagas disease seropositive children.
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http://dx.doi.org/10.3390/tropicalmed6020072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167768PMC
May 2021

Tumor mutational burden assessment in non-small-cell lung cancer samples: results from the TMB harmonization project comparing three NGS panels.

J Immunother Cancer 2021 May;9(5)

H12O-CNIO Lung Cancer Clinical Research Unit, Health Research Institute Hospital 12 de Octubre (imas12) / Spanish National Cancer Research Center (CNIO), Madrid, Spain.

Background: Tumor mutational burden (TMB) is a recently proposed predictive biomarker for immunotherapy in solid tumors, including non-small cell lung cancer (NSCLC). Available assays for TMB determination differ in horizontal coverage, gene content and algorithms, leading to discrepancies in results, impacting patient selection. A harmonization study of TMB assessment with available assays in a cohort of patients with NSCLC is urgently needed.

Methods: We evaluated the TMB assessment obtained with two marketed next generation sequencing panels: TruSight Oncology 500 (TSO500) and Oncomine Tumor Mutation Load (OTML) versus a reference assay (Foundation One, FO) in 96 NSCLC samples. Additionally, we studied the level of agreement among the three methods with respect to PD-L1 expression in tumors, checked the level of different immune infiltrates versus TMB, and performed an inter-laboratory reproducibility study. Finally, adjusted cut-off values were determined.

Results: Both panels showed strong agreement with FO, with concordance correlation coefficients (CCC) of 0.933 (95% CI 0.908 to 0.959) for TSO500 and 0.881 (95% CI 0.840 to 0.922) for OTML. The corresponding CCCs were 0.951 (TSO500-FO) and 0.919 (OTML-FO) in tumors with <1% of cells expressing PD-L1 (PD-L1<1%; N55), and 0.861 (TSO500-FO) and 0.722 (OTML-FO) in tumors with PD-L1≥1% (N=41). Inter-laboratory reproducibility analyses showed higher reproducibility with TSO500. No significant differences were found in terms of immune infiltration versus TMB. Adjusted cut-off values corresponding to 10 muts/Mb with FO needed to be lowered to 7.847 muts/Mb (TSO500) and 8.380 muts/Mb (OTML) to ensure a sensitivity >88%. With these cut-offs, the positive predictive value was 78.57% (95% CI 67.82 to 89.32) and the negative predictive value was 87.50% (95% CI 77.25 to 97.75) for TSO500, while for OTML they were 73.33% (95% CI 62.14 to 84.52) and 86.11% (95% CI 74.81 to 97.41), respectively.

Conclusions: Both panels exhibited robust analytical performances for TMB assessment, with stronger concordances in patients with negative PD-L1 expression. TSO500 showed a higher inter-laboratory reproducibility. The cut-offs for each assay were lowered to optimal overlap with FO.
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http://dx.doi.org/10.1136/jitc-2020-001904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108670PMC
May 2021

Pulmonary vascular proliferation in patients with severe COVID-19: an autopsy study.

Thorax 2021 Mar 23. Epub 2021 Mar 23.

Pathology, Hospital Ramón y Cajal, Madrid, Spain

Diffuse alveolar damage and thrombi are the most common lung histopathological lesions reported in patients with severe COVID-19. Although some studies have suggested increased pulmonary angiogenesis, the presence of vascular proliferation in COVID-19 lungs has not been well characterised. Glomeruloid-like microscopic foci and/or coalescent vascular proliferations measuring up to 2 cm were present in the lung of 14 out of 16 autopsied patients. These lesions expressed CD31, CD34 and vascular endothelial cadherin. Platelet-derived growth factor receptor-β immunohistochemistry and dual immunostaining for CD34/smooth muscle actin demonstrated the presence of pericytes. These vascular alterations may contribute to the severe and refractory hypoxaemia that is common in patients with severe COVID-19.
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http://dx.doi.org/10.1136/thoraxjnl-2020-216714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992389PMC
March 2021

Molecular Heterogeneity of High Grade Colorectal Adenocarcinoma.

Cancers (Basel) 2021 Jan 10;13(2). Epub 2021 Jan 10.

Department of Pathology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria, 28034 Madrid, Spain.

High grade colorectal carcinomas (HG-CRCs), which comprise 15% of colorectal carcinomas, are underrepresented in reported molecular studies. Clinicopathological, immunohistochemical, and molecular features of 40 HG-CRCs are described. Moreover, glandular and solid areas of 25 tumors were separately analyzed. The expression of MLH1, PMS2, MSH2, MSH6, p53, E-cadherin, CDX2, CK20, CD8, PDL1, PAN-TRK, c-MET, SMARCB1, ARID1A, SMARCA2, and SMARCA4 was analyzed by immunohistochemistry. Promoter methylation was analyzed in tumors with MLH1/PMS2 loss. Next-generation sequencing was used to screen 161 genes for hotspot mutations, copy number variations and gene fusions. In this series, 72.5% of HG-CRCs showed mismatch repair deficiency (MMRd). MMR deficient tumor and MMR proficient (MMRp) tumors showed striking molecular differences. Thus, whereas BRAF mutations were only observed in MMRd tumors, mutations in and were more frequent in MMR proficient tumors. Moreover, gene fusions ( and ) were detected only in MMRd tumors, whereas gene amplification (, and ) predominated in MMRp/-mutated tumors. Loss of expression of proteins involved in chromatin remodeling, such as ARID1A, was observed only in MMRd HG-CRCs, which also showed more frequently PD-L1 expression and a higher number of tumor infiltrating lymphocytes. The separate analysis of glandular and solid areas indicated that the clonal or subclonal nature of the molecular alterations also depended on MMR status. Mutations in genes such as and were always clonal in MMRp-CRCs but occurred as subclonal events in MMRd-CRCs. Gene amplification was implicated in the progression of MMRp tumors, but not in MMRd tumors, in which clonal diversity was due to accumulation of mutations in genes of different pathways such as , MMR, or . In summary, intertumor and intratumor molecular heterogeneity in HG-CRCs is mainly due to MMR status.
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http://dx.doi.org/10.3390/cancers13020233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826680PMC
January 2021

Vulvar Pilomatrix Carcinoma: Morphologic and Molecular Features.

Int J Gynecol Pathol 2020 Nov 24. Epub 2020 Nov 24.

Departments of Pathology (D.B.) Gynecology (M.C.S.M.) Oncology (C.S.S), Hospital Ramón y Cajal Department of Pathology, Hospital Ramón y Cajal, Madrid; IRYCIS (T.C.C.) Department of Pathology, Hospital Ramón y Cajal; IRYCIS; CIBER-ONC Carlos III Health Institute; Faculty of Medicine, University of Alcalá de Henares (J.P., B.P.M.), Madrid, Spain.

Pilomatrix carcinoma (PC) is a rare malignant variant of pilomatrixoma, a skin adnexal tumor originating from hair matrix cells. It is most often located in the head, neck region, upper back and upper extremities. PC has a locally aggressive behavior but metastasis only occur in 10% of cases. Mutations in CTNNB1, the encoding gene of beta-catenin, have been found in both pilomatrixoma and PC, but other molecular alterations are unknown. The authors present a case of PC in the clitoris, the third known reported case located on the external genitalia. The tumor followed an unusual clinical course with the development of multiple metastases. Next-generation sequencing analysis of the tumor identified, in addition to a characteristic CTNNB1 mutation, pathogenic mutations in PTEN, PIK3CA, and ARID1A, which could explain the aggressive course of the disease. The diagnostic criteria of PC and the differential diagnoses of this unusual tumor in the genital area are discussed.
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http://dx.doi.org/10.1097/PGP.0000000000000726DOI Listing
November 2020

Morphological and molecular heterogeneity of epithelial ovarian cancer: Therapeutic implications.

EJC Suppl 2020 Aug 22;15:1-15. Epub 2020 Aug 22.

Institute Ramón y Cajal for Health Research, Madrid, Spain.

Ovarian epithelial cancer (OEC) is the most lethal gynecologic malignancy. Despite current chemotherapeutic and surgical options, this high lethality can be attributed to multiple factors, including late-stage presentation. In order to optimize OEC treatment, it is important to highlight that it is composed of five main subtypes: high-grade serous ovarian carcinoma (HGSOC), low-grade serous ovarian carcinoma (LGSOC), endometrioid ovarian carcinoma (EOC), ovarian clear cell carcinoma (CCOC), and mucinous ovarian carcinoma (MOC). These subtypes differ in their precursor lesions, as well as in epidemiological, morphological, molecular and clinical features. OEC is one of the tumours in which most pathogenic germline mutations have been identified. Accordingly, up to 20% OC show alterations in genes, and also, although with a lower frequency, in other low penetrance genes associated with homologous recombination deficiency (HRD), mismatch repair genes (Lynch syndrome) and . The most important prognostic factor is the 2014 FIGO staging, while older age is also associated with worse survival. HGSOC in all stages and CCC and MOC in advanced stages have the worse prognosis among histological types. Molecular markers have emerged as prognostic factors, particularly mutations in which are associated with a better outcome. Regarding treatment, whereas a proportion of HGSOC is sensible to platinum-based treatment and PARP inhibitors due to HRD, the rest of the histological types are relatively chemoresistant. New treatments based in specific molecular alterations are being tested in different histological types. In addition, immunotherapy could be an option, especially for EOC carrying mismatch repair deficiency or mutations.
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http://dx.doi.org/10.1016/j.ejcsup.2020.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573476PMC
August 2020

Giant benign teratoma occupying the left hemithorax with pleural effusion: a rare presentation.

J Surg Case Rep 2020 Sep 14;2020(9):rjaa294. Epub 2020 Sep 14.

Department of Pathological Anatomy, Guillermo Almenara Irigoyen National Hospital, Lima, Peru.

Mature teratomas are the third most common mediastinal tumors. Giant teratoma in pediatric population is rare. A resection of giant benign teratoma in left hemithorax was performed in a 4-year-old patient. The computed tomography scan showed the presence of a large multiloculated mediastinal mass extending to the left pleural space and pleural effusion. The patient underwent total resection of the mediastinal mass via a median sternotomy associated to left anterior thoracotomy. Entry into the pleural space was performed through the sixth intercostal space to obtain safe visualization of the cavity and proceed to tumor excision. The collapsed left lung was re-expanded, and the patient was extubated. Despite the size and the surrounding structures of the teratoma, our preoperative preparation and surgical technique were effective and resulted in favorable recovery without complications and a posterior normal left lung function.
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http://dx.doi.org/10.1093/jscr/rjaa294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490150PMC
September 2020

[A proposal of the Chilean Academy of Medicine to improve organ procurement and transplantation in Chile].

Rev Med Chil 2020 Mar;148(3):381-386

Sociedad Chilena de Trasplantes, Chile.

The Chilean Academy of Medicine designated a group of specialists to evaluate the practice and to propose reforms for organ donation and transplantation, due to the general insufficiencies at the national level with these procedures. In the last six years the mean number of organ transplants in Chile was 340 cases per year while effective cadaveric donors ranged between 6 and 10 per million inhabitants. These averages remained stable during this period and are among the lowest in the region. Our analysis attributed these deficient results mainly to low organ donation and inefficient procurement due to lack of compliance with protocols and little accountability. The committee proposes several measures for improvement. These are a systematic and obligatory report of potential organ donors by all emergency and critical care centers, frequent evaluation of results, empowering of health authorities to correct insufficiencies in organ procurement, education programs for primary, secondary, technical and university students to improve their knowledge about the social significance and solidarity required for transplantation policies and specialized updated training of all health professionals involved. Organ donation and transplantation must be based on clear and fair ethical considerations in order to be accepted by the general public.
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http://dx.doi.org/10.4067/S0034-98872020000300381DOI Listing
March 2020

Rhizobium ruizarguesonis sp. nov., isolated from nodules of Pisum sativum L.

Syst Appl Microbiol 2020 Jul 17;43(4):126090. Epub 2020 May 17.

Centro de Biotecnología y Genómica de Plantas (CBGP), Universidad Politécnica de Madrid - Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, 28223 Pozuelo de Alarcón, Madrid, Spain; Instituto de Ciencias Agrarias, Consejo Superior de Investigaciones Científicas (ICA-CSIC), 28006 Madrid, Spain. Electronic address:

Four strains, coded as UPM1132, UPM1133, UPM1134 and UPM1135, and isolated from nodules of Pisum sativum plants grown on Ni-rich soils were characterised through a polyphasic taxonomy approach. Their 16S rRNA gene sequences were identical and showed 100% similarity with their closest phylogenetic neighbors, the species included in the 'R. leguminosarum group': R. laguerreae FB206, R. leguminosarum USDA 2370, R. anhuiense CCBAU 23252, R. sophoreae CCBAU 03386, R. acidisoli FH13 and R. hidalgonense FH14, and 99.6% sequence similarity with R. esperanzae CNPSo 668. The analysis of combined housekeeping genes recA, atpD and glnII sequences showed similarities of 92-95% with the closest relatives. Whole genome average nucleotide identity (ANI) values were 97.5-99.7% ANIb similarity among the four strains, and less than 92.4% with closely related species, while digital DNA-DNA hybridization average values (dDDH) were 82-85% within our strains and 34-52% with closely related species. Major fatty acids in strain UPM1133 were C18:1 ω7c / C18:1 ω6c in summed feature 8, C14:0 3OH/ C16:1 iso I in summed feature 2 and C18:0. Colonies were small to medium, pearl-white coloured in YMA at 28°C and growth was observed in the ranges 8-34°C, pH 5.5-7.5 and 0-0.7% (w/v) NaCl. The DNA G+C content was 60.8mol %. The combined genotypic, phenotypic and chemotaxonomic data support the classification of strains UPM1132, UPM1133, UPM1134 and UPM1135 into a novel species of Rhizobium, for which the name Rhizobium ruizarguesonis sp. nov. is proposed. The type strain is UPM1133 (=CECT 9542=LMG 30526).
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http://dx.doi.org/10.1016/j.syapm.2020.126090DOI Listing
July 2020

Next generation sequencing to decipher concurrent loss of PMS2 and MSH6 in colorectal cancer.

Diagn Pathol 2020 Jul 14;15(1):84. Epub 2020 Jul 14.

Department of Pathology, Hospital Universitario Ramón y Cajal, Carr de Colmenar Viejo, km. 9,100, 28034, Madrid, Spain.

Background: Immunohistochemistry (IHQ) is commonly used for the detection of mismatch repair proteins deficiency (MMRD). One very infrequent abnormal pattern of MMR protein expression is the loss of PMS2 and MSH6, with intact expression of MLH1 and MSH2.

Case Presentation: We review the frequency of this MMRD IHC pattern among 108 colorectal (CRCs) and 35 endometrial cancers in our files with loss of expression of at least one protein, and present two CRCs showing loss of PMS2 and MSH6 protein expression (1.9% of CRCs). NGS analysis of these tumours identified PMS2 mutations (R134* germline mutation in one tumour and M1R and c.1239delA somatic mutation in the other) as the primary event and somatic MSH6 mutation (c.3261dupC) as the secondary event in both tumours.

Conclusions: This study suggests that Next Generation Sequencing (NGS) tumour analysis should be considered in the algorithm of Lynch syndrome screening to detect MMR gen somatic mutation in inconclusive cases.
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http://dx.doi.org/10.1186/s13000-020-01001-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362514PMC
July 2020

Molecular Features of Metaplastic Breast Carcinoma: An Infrequent Subtype of Triple Negative Breast Carcinoma.

Cancers (Basel) 2020 Jul 8;12(7). Epub 2020 Jul 8.

Pathology Department, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain.

Metaplastic breast carcinoma (MBC) is a heterogeneous group of infrequent invasive carcinomas that display differentiation of the neoplastic epithelium towards squamous cells and/or mesenchymal-type elements. Most MBC have a triple negative phenotype and poor prognosis. Thus, MBC have worse survival rates than other invasive breast carcinomas, including other triple negative breast carcinomas (TNBC). In this study, we reviewed the molecular features of MBC, pointing out the differences among subtypes. The most frequently mutated genes in MBC were and . Additionally, mutations in the other genes of the PI3K/AKT pathway indicated its importance in the pathogenesis of MBC. Regarding copy number variations (CNVs), was the most frequently amplified gene, and the most frequent gene loss affected the locus. Furthermore, the pattern of mutations and CNVs of MBC differed from those reported in other TNBC. However, the molecular profile of MBC was not homogeneous among histological subtypes, being the alterations in the PI3K pathway most frequent in spindle cell carcinomas. Transcriptomic studies have demonstrated an epithelial to mesenchymal program activation and the enrichment of stemness genes in most MBC. In addition, current studies are attempting to define the immune microenvironment of these tumors. In conclusion, due to specific molecular features, MBC have a different clinical behavior from other types of TNBC, being more resistant to standard chemotherapy. For this reason, new therapeutic approaches based on tumor molecular characteristics are needed to treat MBC.
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http://dx.doi.org/10.3390/cancers12071832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408634PMC
July 2020

Development and Validation of the Gene Expression Predictor of High-grade Serous Ovarian Carcinoma Molecular SubTYPE (PrOTYPE).

Clin Cancer Res 2020 10 17;26(20):5411-5423. Epub 2020 Jun 17.

Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia.

Purpose: Gene expression-based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features.

Experimental Design: Adopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting.

Results: Gene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with >95% accuracy that was maintained in all analytic and biological validations.

Conclusions: We validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications..
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572656PMC
October 2020

Low Prevalence of HER2-Positive Breast Carcinomas among Screening Detected Breast Cancers.

Cancers (Basel) 2020 Jun 15;12(6). Epub 2020 Jun 15.

Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, 28029 Madrid, Spain.

Conflicting results have been reported regarding the prevalence of screen-detected human epidermal growth factor receptor 2 (HER2)-positive breast carcinomas and non-screen detected HER2-positive breast carcinomas. To address this issue, we evaluated the prevalence of HER2-positive breast carcinomas in two independent regional screening programs in Spain. The clinicopathologic and immunohistochemical characteristics of 479 (306 and 173) screen-detected breast carcinomas and 819 (479 and 340) non-screen-detected breast carcinomas diagnosed in women between 50 and 69-year-olds were compared. The prevalence of HER2-positive breast carcinomas was 8.8% and 6.4% in the two series of screen-detected tumors, compared with 16.4% and 13% in non-screen-detected carcinomas. These differences were statistically significant. This lower prevalence of HER2-positive in-screen-detected breast carcinomas was observed in both hormone receptor positive (luminal HER2) and hormone-receptor-negative (HER2 enriched) tumors. In addition, a lower prevalence of triple-negative and a higher prevalence of luminal-A breast carcinomas was observed in screen-detected tumors. Moreover, a literature review pointed out important differences in subrogate molecular types in screen-detected breast carcinomas among reported series, mainly due to study design, technical issues and racial differences.
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http://dx.doi.org/10.3390/cancers12061578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352518PMC
June 2020

Molecular Heterogeneity of Endometrioid Ovarian Carcinoma: An Analysis of 166 Cases Using the Endometrial Cancer Subrogate Molecular Classification.

Am J Surg Pathol 2020 07;44(7):982-990

Institute Ramón y Cajal for Health Research (IRYCIS).

Endometrioid ovarian carcinoma (EOC) has clinical and biological differences compared with other histologic types of ovarian carcinomas, but it shares morphologic and molecular features with endometrioid endometrial carcinoma. To analyze the molecular heterogeneity of EOC according to the new molecular classification of endometrial cancer and to evaluate the prognostic significance of this molecular classification, we have analyzed 166 early-stage EOC by immunohistochemistry for mismatch repair proteins and p53 expression, and by Sanger sequencing for the exonuclease domain of polymerase epsilon (POLE EDM). In addition, we have carried out next-generation sequencing analysis of tumors with POLE EDM mutations to confirm the ultramutated profile. Eight tumors carried POLE EDM mutations and were classified as ultramutated (5%), 29 showed mismatch repair deficiency and were classified as hypermutated (18%), 16 tumors had a mutated pattern of p53 expression and were classified as p53 abnormal (11%), and 114 tumors did not have any of the previous alterations and were classified as no specific type (66%). Five tumors showed >1 classification criteria. The frequencies of ultramutated and hypermutated tumors were lower in EOC compared with the frequency reported in endometrial cancer. Subrogate molecular groups differed in both morphologic features (histologic grade, squamous and morular metaplasia, and necrosis) and immunohistochemical expression of several biomarkers (ARID1A, nuclear β-catenin, estrogen receptors, Napsin A, and HINF1B). In addition, the number of CD8 tumor-infiltrating lymphocytes was higher in ultramutated and hypermutated tumors. The most commonly mutated genes in the ultramutated group were ARID1A (100%), PIK3R1, PTEN, BCOR, and TP53 (67% each), whereas no mutations were detected in KRAS. Although the prognosis did not differ among subgroups in the multivariate analysis, a trend toward a better prognosis in POLE-mutated and a worse prognosis in p53 abnormal tumors was observed. In addition, this classification could have important therapeutic implications for the use of immunotherapy in tumors classified as ultramutated and hypermutated.
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http://dx.doi.org/10.1097/PAS.0000000000001478DOI Listing
July 2020

Mismatch Repair Deficiency in Ovarian Carcinoma: Frequency, Causes, and Consequences.

Am J Surg Pathol 2020 05;44(5):649-656

Institute Ramón y Cajal for Health Research.

Mismatch repair deficiency (MMRD) is involved in the initiation of both hereditary and sporadic tumors. MMRD has been extensively studied in colorectal cancer and endometrial cancer, but not so in other tumors, such as ovarian carcinoma. We have determined the expression of mismatch repair proteins in a large cohort of 502 early-stage epithelial ovarian carcinoma entailing all the 5 main subtypes: high-grade serous carcinoma, endometrioid ovarian carcinoma (EOC), clear cell carcinoma (CCC), mucinous carcinoma, and low-grade serous carcinoma. We studied the association of MMRD with clinicopathologic and immunohistochemical features, including tumor-infiltrating lymphocytes in EOC, the histologic type in which MMRD is most frequent. In addition, MLH1 promoter methylation status and massive parallel sequencing were used to evaluate the proportion of sporadic and Lynch syndrome-associated tumors, and the most frequently mutated genes in MMRD EOCs. MMRD occurred only in endometriosis-associated histologic types, and it was much more frequent in EOC (18%) than in CCC (2%). The most frequent immunohistochemical pattern was loss of MLH1/PMS2, and in this group, 80% of the cases were sporadic and secondary to MLH1 promoter hypermethylation. The presence of somatic mutations in mismatch repair genes was the other mechanism of MMRD in sporadic tumors. In this series, the minimum estimated frequency of Lynch syndrome was 35% and it was due to germline mutations in MLH1, MSH2, and MSH6. ARID1A, PTEN, KTM2B, and PIK3CA were the most common mutated genes in this series. Interestingly, possible actionable mutations in ERRB2 were found in 5 tumors, but no TP53 mutations were detected. MMRD was associated with younger age and increased tumor-infiltrating lymphocytes. Universal screening in EOC and mixed EOC/CCC is recommended for the high frequency of MMRD detected; however, for CCC, additional clinical and pathologic criteria should be evaluated to help select cases for analysis.
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http://dx.doi.org/10.1097/PAS.0000000000001432DOI Listing
May 2020

The PALBONET Trial: A Phase II Study of Palbociclib in Metastatic Grade 1 and 2 Pancreatic Neuroendocrine Tumors (GETNE-1407).

Oncologist 2020 09 11;25(9):745-e1265. Epub 2020 Feb 11.

Department of Medical Oncology, University Hospital 12 de Octubre, IIS imas12, UCM, CNIO, CIBERONC, Madrid, Spain.

Lessons Learned: Palbociclib demonstrated no detectable activity in molecularly unselected and heavily pretreated patients with advanced grade 1/2 pancreatic neuroendocrine tumors. Predictive biomarkers that improve patient selection should be investigated in future studies of palbociclib.

Background: Palbociclib, a CDK4/6 inhibitor, has shown in vitro activity in pancreatic neuroendocrine tumor (pNET) cell lines. Here we prospectively assessed the activity and safety of palbociclib in monotherapy in metastatic refractory pNETs.

Methods: This was a nonrandomized, open-label, phase II study of patients with metastatic grade (G)1/2 pNETs recruited from 10 centers in Spain. Palbociclib 125 mg was orally administered once daily for 21 of 28 days until disease progression or unacceptable toxicity.

Results: Twenty-one patients were included; 52.4% were men, and median age was 57.4 years (range, 37.4-73.4). Patients had previously received a median of three prior lines of systemic therapy (range, 1-10) for advanced disease (somatostatin analogues, 71.4%; sunitinib, 81.0%; everolimus, 47.6%; chemotherapy, 47.6%). Nineteen patients were evaluated for objective response rate (ORR), with a median follow-up of 12.4 months (range, 7.53-19.33). No objective and confirmed responses were observed (0%); 11 (57.9%) patients had stable disease, and 6 of them lasted more than 6 months; 8 (42.1%) patients had disease progression as best response. Median progression-free survival (PFS) was 2.6 months (95% confidence interval [CI], 0-14.4) and median overall survival (OS) was 18.7 months (95% CI, 7.4-29.9; Fig. 1). Most frequent toxicities of any grade were asthenia (76.2%), neutropenia (42.9%), diarrhea (33.3%), and nausea (33.3%). Five (23.8%) patients developed G3-4 neutropenia and two (9.5%) patients developed G3-4 thrombocytopenia.

Conclusion: Lack of activity was observed with palbociclib as a single agent in molecularly unselected and heavily pretreated patients with advanced G1/2 pNETs.
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http://dx.doi.org/10.1634/theoncologist.2020-0033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485337PMC
September 2020

Hydrogen-uptake genes improve symbiotic efficiency in common beans (Phaseolus vulgaris L.).

Antonie Van Leeuwenhoek 2020 May 3;113(5):687-696. Epub 2020 Jan 3.

Embrapa Soja, Cx. Postal 231, Londrina, PR, 86001-970, Brazil.

Hydrogen-uptake (Hup) activity is implicated in the mitigation of energy losses associated with the biological nitrogen fixation process, and has been related to productivity increases in some legume hosts. However, in common bean (Phaseolus vulgaris L.) the expression of hydrogenase is rare. In this study an 18-kb hup gene cluster from Rhizobium leguminosarum bv. viciae encoding a NiFe hydrogenase was successfully transferred to three common bean rhizobial strains lacking hydrogenase activity (Hup) but symbiotically very effective and used in commercial inoculants in Brazil: one strain originally from Colombia (Rhizobium tropici CIAT 899), and two strains from Brazil (R. tropici H 12 and Rhizobium freirei PRF 81). The inclusion of NiCl in the nutrient solution did not increase hydrogenase activity, indicating that common bean plants allow efficient nickel provision for hydrogenase synthesis in the bacteroids. The symbiotic performance-evaluated by nodulation, plant growth, N accumulation and seed production-of wild-type and Hup derivative strains was compared in experiments performed with cultivar Carioca under greenhouse conditions, in sterile substrate and in non-sterile soil. Statistically significant increases in one or more parameters were observed for all three Hup derivatives when compared to the respective wild-type strain. Differences were found mainly with the Brazilian strains, reaching impressive increases in nodule efficiency and seed total N content. The results highlight the potential of using Rhizobium Hup strains for the design of more energy-efficient inoculants for the common bean crop.
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http://dx.doi.org/10.1007/s10482-019-01381-6DOI Listing
May 2020

Financial Hardship, Motivation to Quit and Post-Quit Spending Plans among Low-Income Smokers Enrolled in a Smoking Cessation Trial.

Subst Abuse 2019 9;13:1178221819878765. Epub 2019 Oct 9.

Department of Population Health, New York University School of Medicine, New York, NY, USA.

Background: Tobacco spending may exacerbate financial hardship in low-income populations by using funds that could go toward essentials. This study examined post-quit spending plans among low-income smokers and whether financial hardship was positively associated with motivation to quit in the sample.

Methods: We analyzed data from the baseline survey of a randomized controlled trial testing novel a smoking cessation intervention for low-income smokers in New York City ( = 410). Linear regression was used to examine the relationship between financial distress, food insecurity, smoking-induced deprivation (SID) and motivation to quit (measured on a 0-10 scale). We performed summative content analyses of open-ended survey questions to identify the most common plans among participants with and without SID for how to use their tobacco money after quitting.

Results: Participants had an average level of motivation to quit of 7.7 ( = 2.5). Motivation to quit was not significantly related to having high financial distress or food insecurity ( > .05), but participants reporting SID had significantly lower levels of motivation to quit than those without SID ( = 7.4 versus 7.9, = .04). Overall, participants expressed an interest in three main types of spending for after they quit: , and , which could be further conceptualized as spending on , and on The top three spending plans among participants with and without SID were travel, clothing and savings. There were three needs-based spending plans unique to a small number of participants with SID: housing, health care and education.

Conclusions: Financial distress and food insecurity did not enhance overall motivation to quit, while smokers with SID were less motivated to quit. Most low-income smokers, including those with SID, did not plan to use their tobacco money on household essentials after quitting.
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http://dx.doi.org/10.1177/1178221819878765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785910PMC
October 2019

Microvirga tunisiensis sp. nov., a root nodule symbiotic bacterium isolated from Lupinus micranthus and L. luteus grown in Northern Tunisia.

Syst Appl Microbiol 2019 Nov 23;42(6):126015. Epub 2019 Sep 23.

Centro de Biotecnología y Genómica de Plantas, Universidad Politécnica de Madrid (UPM) - Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA), Campus Montegancedo UPM, Pozuelo de Alarcón, Madrid, 28223, Spain; Departamento de Biotecnología-Biología Vegetal, Escuela Técnica Superior de Ingeniería Agronómica, Alimentaria y de Biosistemas, UPM, Madrid, 28040, Spain; Instituto de Ciencias Agrarias, CSIC, Madrid, 28006, Spain. Electronic address:

Three bacterial strains, LmiM8, LmiE10 and LluTb3, isolated from nitrogen-fixing nodules of Lupinus micranthus (Lmi strains) and L. luteus (Llu strain) growing in Northern Tunisia were analysed using genetic, phenotypic and symbiotic approaches. Phylogenetic analyses based on rrs and concatenated gyrB and dnaK genes suggested that these Lupinus strains constitute a new Microvirga species with identities ranging from 95 to 83% to its closest relatives Microvirga makkahensis, M. vignae, M. zambiensis, M. ossetica, and M. lotononidis. The genome sequences of strains LmiM8 and LmiE10 exhibited pairwise Average Nucleotide Identities (ANIb) above 99.5%, significantly distant (73-89% pairwise ANIb) from other Microvirga species sequenced (M. zambiensis and M. ossetica). A phylogenetic analysis based on the symbiosis-related gene nodA placed the sequences of the new species in a divergent clade close to Mesorhizobium, Microvirga and Bradyrhizobium strains, suggesting that the M. tunisiensis strains represent a new symbiovar different from the Bradyrhizobium symbiovars defined to date. In contrast, the phylogeny derived from another symbiosis-related gene, nifH, reproduced the housekeeping genes phylogenies. The study of morphological, phenotypical and physiological features, including cellular fatty acid composition of the novel isolates demonstrated their unique profile regarding close reference Microvirga strains. Strains LmiM8, LmiE10 and LluTb3 were able to nodulate several Lupinus spp. Based on genetic, genomic and phenotypic data presented in this study, these strains should be grouped within a new species for which the name Microvirga tunisiensis sp. nov. is proposed (type strain LmiM8=CECT 9163, LMG 29689).
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http://dx.doi.org/10.1016/j.syapm.2019.126015DOI Listing
November 2019

[Clinical challenges and implications of intratumor heterogeneity].

Rev Esp Patol 2019 Oct - Dec;52(4):234-241. Epub 2019 Jun 6.

Servicio de Anatomía Patológica, Hospital Universitario Cruces, Instituto Biocruces-Bizkaia, Universidad del País Vasco (UPV/EHU), Barakaldo, Vizcaya, España; Servicio de Anatomía Patológica, Hospital Universitario Cruces, Instituto Biocruces-Bizkaia, Universidad del País Vasco (UPV/EHU), Barakaldo, Vizcaya, España. Electronic address:

Tumors display a high, albeit variable, grade of intratumor heterogeneity, both from a clinical and a morphological viewpoint. Furthermore, recent methods of large-scale molecular analysis demonstrate to what extent tumors can also be heterogeneous from a molecular perspective. This is of paramount importance for patients as it has a great impact on the success of so-called precision therapies and explains the reason for a significant number of therapeutic failures in modern oncology. We present an up-to-date review of the latest findings in a group of tumors with a high social impact, commonly seen in the daily routine of the pathology laboratory.
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http://dx.doi.org/10.1016/j.patol.2019.04.004DOI Listing
June 2020

The Frequency and Prognostic Significance of the Histologic Type in Early-stage Ovarian Carcinoma: A Reclassification Study by the Spanish Group for Ovarian Cancer Research (GEICO).

Am J Surg Pathol 2020 02;44(2):149-161

Oncogynecologic Department, Initia Oncology, Hospital Quironsalud Valencia, Valencia.

The frequency and prognostic significance of the histologic type in early-stage ovarian cancer (OC) is not as well established as in advanced stages. In addition, histologic typing based only on morphologic features may be difficult, especially in high-grade tumors. In this study, we have analyzed a prospective cohort of 502 early-stage OCs to investigate their frequency, immunohistochemical characteristics, and survival of the 5 main histologic types. Histotype was assigned according to not only the morphologic features but also according to the expression pattern of WT1, p53, Napsin A, and progesterone receptors. In addition, an extended panel including p16, β-catenin, HER2, Arid1A, HINF1B, CK7, CDX2, and CK20 was used to refine the diagnosis in difficult cases. In this series, the frequency of the 5 major histologic types was as follows: endometrioid carcinoma, 32.7%; clear cell carcinoma, 25.1%; high-grade serous carcinoma (HGSC), 24.7%; mucinous carcinoma, 10.2%; low-grade serous carcinoma, 4.6%; and others, 2.8%. The combination of morphology and immunohistochemistry allowed the reclassification of 23% of OCs. The lowest concordance was found between samples initially diagnosed as endometrioid, but finally classified as high-grade serous tumors (22% error rate). Endometrioid carcinoma was the most favorable histologic type, whereas HGSC and low-grade serous carcinoma had the worst prognosis. Clear cell carcinoma with abnormal p53 immunostaining pattern also had poor prognosis. Although histologic grade was not a prognostic factor among early-stage endometrioid OCs, distinction between grade 3 endometrioid OC and HGSC is recommended, taking into account differences in prognosis and molecular alterations that can guide different treatments.
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http://dx.doi.org/10.1097/PAS.0000000000001365DOI Listing
February 2020

Molecular Basis of Tumor Heterogeneity in Endometrial Carcinosarcoma.

Cancers (Basel) 2019 Jul 9;11(7). Epub 2019 Jul 9.

Department of Pathology, Institute Ramón y Cajal for Health Research, 28034 Madrid, Spain.

Endometrial carcinosarcoma (ECS) represents one of the most extreme examples of tumor heterogeneity among human cancers. ECS is a clinically aggressive, high-grade, metaplastic carcinoma. At the morphological level, intratumor heterogeneity in ECS is due to an admixture of epithelial (carcinoma) and mesenchymal (sarcoma) components that can include heterologous tissues, such as skeletal muscle, cartilage, or bone. Most ECSs belong to the copy-number high serous-like molecular subtype of endometrial carcinoma, characterized by the mutation and the frequently accompanied by a large number of gene copy-number alterations, including the amplification of important oncogenes, such as and . However, a proportion of cases (20%) probably represent the progression of tumors initially belonging to the copy-number low endometrioid-like molecular subtype (characterized by mutations in genes such as , or ), after the acquisition of the mutations. Only a few ECS belong to the microsatellite-unstable hypermutated molecular type and the -mutated, ultramutated molecular type. A common characteristic of all ECSs is the modulation of genes involved in the epithelial to mesenchymal process. Thus, the acquisition of a mesenchymal phenotype is associated with a switch from E- to N-cadherin, the up-regulation of transcriptional repressors of E-cadherin, such as Snail Family Transcriptional Repressor 1 and 2 (SNAI1 and SNAI2), Zinc Finger E-Box Binding Homeobox 1 and 2 (ZEB1 and ZEB2), and the down-regulation, among others, of members of the miR-200 family involved in the maintenance of an epithelial phenotype. Subsequent differentiation to different types of mesenchymal tissues increases tumor heterogeneity and probably modulates clinical behavior and therapy response.
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http://dx.doi.org/10.3390/cancers11070964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678708PMC
July 2019

Intracellular Delivery of an Antibody Targeting Gasdermin-B Reduces HER2 Breast Cancer Aggressiveness.

Clin Cancer Res 2019 08 7;25(15):4846-4858. Epub 2019 May 7.

Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), IdiPaz, Madrid, Spain.

Purpose: Gasdermin B (GSDMB) overexpression/amplification occurs in about 60% of HER2 breast cancers, where it promotes cell migration, resistance to anti-HER2 therapies, and poor clinical outcome. Thus, we tackle GSDMB cytoplasmic overexpression as a new therapeutic target in HER2 breast cancers.

Experimental Design: We have developed a new targeted nanomedicine based on hyaluronic acid-biocompatible nanocapsules, which allow the intracellular delivery of a specific anti-GSDMB antibody into HER2 breast cancer cells both and .

Results: Using different models of HER2 breast cancer cells, we show that anti-GSDMB antibody loaded to nanocapsules has significant and specific effects on GSDMB-overexpressing cancer cells' behavior in ways such as (i) lowering the cell migration induced by GSDMB; (ii) enhancing the sensitivity to trastuzumab; (iii) reducing tumor growth by increasing apoptotic rate in orthotopic breast cancer xenografts; and (iv) diminishing lung metastasis in MDA-MB-231-HER2 cells . Moreover, at a mechanistic level, we have shown that AbGB increases GSDMB binding to sulfatides and consequently decreases migratory cell behavior and may upregulate the potential intrinsic procell death activity of GSDMB.

Conclusions: Our findings portray the first evidence of the effectiveness and specificity of an antibody-based nanomedicine that targets an intracellular oncoprotein. We have proved that intracellular-delivered anti-GSDMB reduces diverse protumor GSDMB functions (migration, metastasis, and resistance to therapy) in an efficient and specific way, thus providing a new targeted therapeutic strategy in aggressive HER2 cancers with poor prognosis.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-2381DOI Listing
August 2019

The Type VI secretion system of Rhizobium etli Mim1 has a positive effect in symbiosis.

FEMS Microbiol Ecol 2019 05;95(5)

Centro de Biotecnología y Genómica de Plantas, Universidad Politécnica de Madrid (UPM)-Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA), Campus de Montegancedo, 28223 Madrid, Spain.

The Type VI secretion systems (T6SSs) allow bacteria to translocate effector proteins to other bacteria or to eukaryotic cells. However, little is known about the role of T6SS in endosymbiotic bacteria. In this work we describe the T6SS of Rhizobium etli Mim1, a bacteria able to effectively nodulate common beans. Structural genes and those encoding possible effectors have been identified in a 28-gene DNA region of R. etli Mim1 pRetMIM1f plasmid. Immunodetection of Hcp protein, a conserved key structural component of T6SS systems, indicates that this secretion system is active at high cell densities, in the presence of root exudates, and in bean nodules. Rhizobium etli mutants affected in T6SS structural genes produced plants with lower dry weight and smaller nodules than the wild-type strain, indicating for the first time that the T6SS plays a positive role in Rhizobium-legume symbiosis.
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http://dx.doi.org/10.1093/femsec/fiz054DOI Listing
May 2019

Efficacy of immunotherapy in sarcomatoid lung cancer, a case report and literature review.

Respir Med Case Rep 2019 20;26:310-314. Epub 2019 Feb 20.

Thoracic Oncology Department, Universitary Hospital Ramon y Cajal, Madrid, Spain.

Sarcomatoid carcinoma is a subtype of non-small cell lung cancer (NSCLC) characterized by mesenchymal - epithelial transition component and awful prognosis. In this report, based on a case of stage IV lung sarcomatoid carcinoma with an extraordinary evolution and survival over 4 years, we address unresolved questions about the treatment of this cancer. We also make a literature review about the key factors that characterize this histology and that should be considered when treating those patients. Sarcomatoid carcinoma presents with mutations as KRAS, EGFR, ALK or MET in up to 70% of cases, and an important expression of PD-L1 (also called B7-H1), which can influence treatment of those patients with new drugs as immune checkpoint inhibitors. Immunotherapy has changed the horizon of patients with stage IV lung cancers without driver mutations, as their survival has improved extraordinary. Moreover, radical treatments are being considered in long survivors with oligometastatic disease. In this report, we review targeted and radical therapy, treatment duration and the mechanisms responsible of disease evolution of sarcomatoid tumors.
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http://dx.doi.org/10.1016/j.rmcr.2019.02.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409391PMC
February 2019

Urethral regions with differential tissular composition may underlie urinary continence and voiding function in female rats.

Neurourol Urodyn 2019 03 19;38(3):893-901. Epub 2019 Feb 19.

Centro Tlaxcala de Biología de la Conducta, Universidad Autónoma de Tlaxcala, Tlaxcala, México.

Aims: To analyze, in female rats, the anatomical and histological features of the urethra and its relationship with the vagina and clitoris, and its innervation.

Methods: Seventeen adult female Wistar rats were used. Gross anatomy and acetylcholinesterase (AchE) histochemistry were performed to describe the urethral features, adjacent structures, and innervation. The histomorphometric characteristics of the urethra were determined in transversal, longitudinal, or coronal sections stained with Masson's Trichrome.

Results: The female rat urethra is not a homogeneous tubular organ. The pre-pelvic and pelvic regions are firmly attached to the vagina with belt-like striated fibers forming a urethra-vaginal complex. The bulbar regions have curved segments and a narrow lumen. The clitoral region is characterized by a urethra-clitoral complex surrounded by a vascular plexus. The lumen area and thickness of the urethral layers significantly varied between regions (P < 0.05). Innervation of the urethra arrives from the major pelvic ganglion, the dorsal nerve of the clitoris (DNC), and the motor branch of the sacral plexus (MBSP).

Conclusions: Differential tissular composition of the urethra may underlie urinary continence and voiding dysfunction through different physiological mechanisms. The urethra-vagina complex seems to be the main site controlling urinary continence through active muscular mechanisms, while the bulbar urethra provides passive mechanisms and the urethra-clitoris complex seems to be crucial for distal urethral closure by means of a periurethral vascular network.
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http://dx.doi.org/10.1002/nau.23934DOI Listing
March 2019

Computational analyses, molecular dynamics, and mutagenesis studies of unprocessed form of [NiFe] hydrogenase reveal the role of disorder for efficient enzyme maturation.

Biochim Biophys Acta Bioenerg 2019 04 29;1860(4):325-340. Epub 2019 Jan 29.

Centro de Biotecnología y Genómica de Plantas (C.B.G.P.) UPM-INIA, Universidad Politécnica de Madrid, Campus de Montegancedo, 28223 Pozuelo de Alarcón, Spain; Departamento de Biotecnología-Biología Vegetal, Escuela Técnica Superior de Ingeniería Agronómica, Alimentaria y de Biosistemas, Universidad Politécnica de Madrid, Madrid, Spain. Electronic address:

Biological production and oxidation of hydrogen is mediated by hydrogenases, key enzymes for these energy-relevant reactions. Synthesis of [NiFe] hydrogenases involves a complex series of biochemical reactions to assemble protein subunits and metallic cofactors required for enzyme function. A final step in this biosynthetic pathway is the processing of a C-terminal tail (CTT) from its large subunit, thus allowing proper insertion of nickel in the unique NiFe(CN)CO cofactor present in these enzymes. In silico modelling and Molecular Dynamics (MD) analyses of processed vs. unprocessed forms of Rhizobium leguminosarum bv. viciae (Rlv) hydrogenase large subunit HupL showed that its CTT (residues 582-596) is an intrinsically disordered region (IDR) that likely provides the required flexibility to the protein for the final steps of proteolytic maturation. Prediction of pKa values of ionizable side chains in both forms of the enzyme's large subunit also revealed that the presence of the CTT strongly modify the protonation state of some key residues around the active site. Furthermore, MD simulations and mutant analyses revealed that two glutamate residues (E27 in the N-terminal region and E589 inside the CTT) likely contribute to the process of nickel incorporation into the enzyme. Computational analysis also revealed structural details on the interaction of Rlv hydrogenase LSU with the endoprotease HupD responsible for the removal of CTT.
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http://dx.doi.org/10.1016/j.bbabio.2019.01.001DOI Listing
April 2019

High Frequency of Activating Mutations in Invasive Lobular Breast Carcinoma with Pleomorphic Features.

Cancers (Basel) 2019 Jan 11;11(1). Epub 2019 Jan 11.

CIBER-ONC, Instituto de Salud Carlos III, 28029 Madrid, Spain.

Characterisation of molecular alterations of pleomorphic lobular carcinoma (PLC), an aggressive subtype of invasive lobular carcinoma (ILC), have not been yet completely accomplished. To investigate the molecular alterations of invasive lobular carcinoma with pleomorphic features, a total of 39 tumour samples (in situ and invasive lesions and lymph node metastases) from 27 patients with nuclear grade 3 invasive lobular carcinomas were subjected to morphological, immunohistochemical and massive parallel sequencing analyses. Our observations indicated that invasive lobular carcinomas with pleomorphic features were morphologically and molecularly heterogeneous. All cases showed absence or aberrant expression of E-cadherin and abnormal expression of β-catenin and p120. (89%), (33%) and (26%) were the most common mutated genes. mutations preferentially affected the tyrosine-kinase activity domain, being the most frequent the targetable mutation p.L755S (57%). We also observed higher frequency of mutations in , , , and in PLC than previously reported in classic ILC. Alterations related to progression from in situ to invasive carcinoma and/or to lymph node metastases included mutation, amplification of and and loss of ARID1A expression. The high frequency of mutations observed suggests that mutation testing should be considered in all invasive lobular carcinomas with nuclear grade 3.
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http://dx.doi.org/10.3390/cancers11010074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356653PMC
January 2019

Pleomorphic lobular carcinoma of the breast with osteoclast-like giant cells: a case report and review of the literature.

Diagn Pathol 2018 Aug 28;13(1):62. Epub 2018 Aug 28.

Department of Pathology, Hospital Ramón y Cajal, Madrid, Spain.

Background: Breast carcinoma with osteoclast-like giant cells (OGCs) is infrequent, being most reported cased described as ductal invasive carcinomas. Invasive pleomorphic lobular carcinoma (PLC) is a distinct morphological variant of invasive lobular carcinoma characterized by higher nuclear atypia and pleomorphism than the classical type. In the best of our knowledge, a PLC with OGCs has not been previously reported.

Case Presentation: We report the case of a 72-year-old woman presenting with a pleomorphic tumor of the left breast with a dense infiltration by OGCs and T lymphocytes with a 10:1 predominance of CD8+ over CD4+ cells. The diagnosis of a lymphoid or mesenchymal neoplasia was excluded after demonstrating keratin expression by the neoplastic cells. The absence of E-cadherin expression and the morphological features were consistent with the diagnosis PLC with OGCs. In addition, we demonstrated the deleterious mutation C.del866C in CDH1gene, but no mutations in any of the other 33 genes analyzed by next generation sequencing.

Conclusions: Breast carcinoma with stromal osteoclast-like giant cells is a very rare tumor, for that reason, the use of the cytologic features and growth patterns in combination with immunohistochemically studies is mandatory for a correct diagnosis of lobular carcinoma. In addition, further studies are necessary to clarify the influence of OGCs in the prognosis of these patients.
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http://dx.doi.org/10.1186/s13000-018-0744-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6114493PMC
August 2018

Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study.

J Pathol Clin Res 2018 10 21;4(4):250-261. Epub 2018 Sep 21.

Cancer Control and Population Sciences, Duke Cancer Institute, Durham, NC, USA.

We aimed to validate the prognostic association of p16 expression in ovarian high-grade serous carcinomas (HGSC) and to explore it in other ovarian carcinoma histotypes. p16 protein expression was assessed by clinical-grade immunohistochemistry in 6525 ovarian carcinomas including 4334 HGSC using tissue microarrays from 24 studies participating in the Ovarian Tumor Tissue Analysis consortium. p16 expression patterns were interpreted as abnormal (either overexpression referred to as block expression or absence) or normal (heterogeneous). CDKN2A (which encodes p16) mRNA expression was also analyzed in a subset (n = 2280) mostly representing HGSC (n = 2010). Association of p16 expression with overall survival (OS) was determined within histotypes as was CDKN2A expression for HGSC only. p16 block expression was most frequent in HGSC (56%) but neither protein nor mRNA expression was associated with OS. However, relative to heterogeneous expression, block expression was associated with shorter OS in endometriosis-associated carcinomas, clear cell [hazard ratio (HR): 2.02, 95% confidence (CI) 1.47-2.77, p < 0.001] and endometrioid (HR: 1.88, 95% CI 1.30-2.75, p = 0.004), while absence was associated with shorter OS in low-grade serous carcinomas (HR: 2.95, 95% CI 1.61-5.38, p = 0.001). Absence was most frequent in mucinous carcinoma (50%), and was not associated with OS in this histotype. The prognostic value of p16 expression is histotype-specific and pattern dependent. We provide definitive evidence against an association of p16 expression with survival in ovarian HGSC as previously suggested. Block expression of p16 in clear cell and endometrioid carcinoma should be further validated as a prognostic marker, and absence in low-grade serous carcinoma justifies CDK4 inhibition.
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http://dx.doi.org/10.1002/cjp2.109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174617PMC
October 2018