Isabel M. Aragón

Instituto de Investigación Biomédica de Málaga

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David Olmos

Hospital Universitario 12 De Octubre

Nuria Romero-Laorden

Universidad Autónoma de Madrid

Elena Castro

Hospital Universitario 12 De Octubre

Rebeca Lozano

Instituto de Investigación Biomédica de Málaga

Cayo Ramos

Instituto de Hortofruticultura Subtropical y Mediterránea "La Mayora"

M.I. Pacheco

Hospital Universitario de La Princesa

Shahneen Sandhu

Peter MacCallum Cancer Centre

Heather Thorne

Peter MacCallum Cancer Centre

Bernardo Herrera‐Imbroda

Hospital Clínico Universitario Virgen de la Victoria

Pedro P. López‐Casas

Hospital Universitario 12 De Octubre

Cooperative Institutions

Instituto de Investigación Biomédica de Málaga

Hospital Clínico Universitario Virgen de la Victoria

Consejo Superior de Investigaciones Científicas

Spanish National Cancer Research Centre

Universidad de Málaga

Institute of Cancer Research

Istituti di Ricovero e Cura a Carattere Scientifico

Royal Marsden NHS Foundation Trust

Universidad Autónoma de Madrid

Instituto de Salud Carlos III

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Association between BRCA2 status and histologic variants (intraductal [IDC] and cribriform [CRIB] histology) in prostate cancer (PC).

Journal of Clinical Oncology (2020)

Elena Castro Daniela C. Salles Rebeca Lozano Heather Thorne Isabel M. Aragón

5579 Background: IDC histology in PC has been suggested to associate with germline BRCA2 mutations (gBRCA2) in small series, leading to the potential recommendation of genetic testing for all PC patients with IDC in the primary tumor. Methods: We conducted a case-control study in which primary PC from 58 germline BRCA2 mutation carriers ( gBRCA2) and 116 from non-carriers (NC) were matched 1:2 by Gleason score and specimen type (core biopsy/prostatectomy). Samples were independently reviewed by two expert pathologists blinded to genetic status who established the presence of IDC and/or CRIB morphology with supportive immunohistochemical stains in a subset of cases. Next-generation sequencing, aCGH and/or FISH were used to assess for somatic mono-/bi-allelic BRCA2 alterations. PTEN protein loss was determined by IHC, and TMPRSS2-ERG was detected by FISH/qRT-PCR. Chi-square tests were used to compare the frequency of IDC and cribriform histology in gBRCA2 vs NC, as well as to assess the associations with other variables. Logistic regression models were built to identify independent factors associated with IDC and CRIB histology. Results: gBRCA2 cases were younger at diagnosis (median 61.3 vs 64, p < 0.01) and had T3-4 disease more often than NC cases (31% vs 10.5%, p < 0.01), but the two groups did not differ in any other clinical-pathologic characteristics. After independent histopathological review, 79 cases demonstrated IDC histology and 81 had CRIB histology. No differences in the prevalence of IDC (50% NC vs 36% gBRCA2, p = 0.09) or CRIB (43% NC vs 53% gBRCA2, p = 0.20) patterns were observed. The probability of IDC was higher in PC with bi-allelic BRCA2 alterations (OR 5.1, 95%CI 2.1-12.6), PTEN loss (OR 5.1, 95%CI 1.9-13.5) or both (OR 23.0, 95%CI 4.9-107.2) compared to those without these alterations. Bi-allelic BRCA2 alteration was also associated with higher probability of CRIB histology (OR 7.2, 95%CI 3.1-16.4). TMPRSS2-ERG fusions were not associated with IDC or CRIB histology. MVA confirmed the independent association of bi-allelic BRCA2 alteration (p < 0.01) and PTEN loss (p < 0.01) with IDC histology. Bi-allelic BRCA2 alteration (p < 0.01) and Gleason >8 (p < 0.01) were independent risk factors for CRIB histology. Conclusions: Primary PC with bi-allelic BRCA2 alterations was significantly associated with IDC and CRIB histology, independent of other clinical-pathologic factors (while gBRCA2 status alone was not). PTEN loss in primary PC was also independently associated with IDC, but not CRIB, histology.

Histology

10.1200/jco.2020.38.15_suppl.5579

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Citations (2)

Risk Prediction Tools Available for Germline BRCA1/2 Mutations Underperform in Prostate Cancer Patients

European Urology Oncology (2019)

L. Martinez Oliva Rebeca Lozano Casilda Llácer Isabel M. Aragón Bella I. Pajares

10.1016/j.euo.2019.06.019

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Citations (9)

The c‐di‐GMP phosphodiesterase BifA is involved in the virulence of bacteria from the Pseudomonas syringae complex

Molecular Plant Pathology (2014)

Isabel M. Aragón Daniel Pérez‐Mendoza Marı́a-Trinidad Gallegos Cayo Ramos

Summary In a recent screen for novel virulence factors involved in the interaction between P seudomonas savastanoi pv. savastanoi and the olive tree, a mutant was selected that contained a transposon insertion in a putative cyclic diguanylate (c‐di‐ GMP ) phosphodiesterase‐encoding gene. This gene displayed high similarity to bifA of P seudomonas aeruginosa and P seudomonas putida . Here, we examined the role of BifA in free‐living and virulence‐related phenotypes of two bacterial plant pathogens in the P seudomonas syringae complex, the tumour‐inducing pathogen of woody hosts, P . savastanoi pv. savastanoi NCPPB 3335, and the pathogen of tomato and A rabidopsis , P . syringae pv. tomato DC 3000. We showed that deletion of the bifA gene resulted in decreased swimming motility of both bacteria and inhibited swarming motility of DC 3000. In contrast, overexpression of BifA in P . savastanoi pv. savastanoi had a positive impact on swimming motility and negatively affected biofilm formation. Deletion of bifA in NCPPB 3335 and DC 3000 resulted in reduced fitness and virulence of the microbes in olive ( NCPPB 3335) and tomato ( DC 3000) plants. In addition, real‐time monitoring of olive plants infected with green fluorescent protein ( GFP )‐tagged P . savastanoi cells displayed an altered spatial distribution of mutant Δ bifA cells inside olive knots compared with the wild‐type strain. All free‐living phenotypes that were altered in both Δ bifA mutants, as well as the virulence of the NCPPB 3335 Δ bifA mutant in olive plants, were fully rescued by complementation with P . aeruginosa BifA , whose phosphodiesterase activity has been demonstrated. Thus, these results suggest that P . syringae and P . savastanoi BifA are also active phosphodiesterases. This first demonstration of the involvement of a putative phosphodiesterase in the virulence of the P . syringae complex provides confirmation of the role of c‐di‐ GMP signalling in the virulence of this group of plant pathogens.

Pseudomonas syringae

Swarming motility

10.1111/mpp.12218

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Citations (31)

Response to fungal exudates of the rhizosphere isolate Pseudomonas sp. UMAF110 involves a GGDEF/EAL domain-containing protein

Adrián Pintado Isabel M. Aragón Isabel Pérez‐Martínez Clara Pliego J. Ignacio Crespo Gómez

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Value of Early Circulating Tumor Cells Dynamics to Estimate Docetaxel Benefit in Metastatic Castration-Resistant Prostate Cancer (mCRPC) Patients

Cancers (2021)

Rebeca Lozano David Lorente Isabel M. Aragón Nuria Romero-Laorden Paz Nombela

Circulating tumor cell (CTC) enumeration and changes following treatment have been demonstrated to be superior to PSA response in determining mCRPC outcome in patients receiving AR signaling inhibitors but not taxanes. We carried out a pooled analysis of two prospective studies in mCRPC patients treated with docetaxel. CTCs were measured at baseline and 3–6 weeks post treatment initiation. Cox regression models were constructed to compare 6-month radiographical progression-free survival (rPFS), CTCs and PSA changes predicting outcome. Among the subjects, 80 and 52 patients had evaluable baseline and post-treatment CTC counts, respectively. A significant association of higher baseline CTC count with worse overall survival (OS), PFS and time to PSA progression (TTPP) was observed. While CTC response at 3–6 weeks (CTC conversion (from ≥5 to <5 CTCs), CTC30 (≥30% decline in CTC) or CTC0 (decline to 0 CTC)) and 6-month rPFS were significantly associated with OS (all p < 0.005), the association was not significant for PSA30 or PSA50 response. CTC and PSA response were discordant in over 50% of cases, with outcome driven by CTC response in these patients. The c-index values for OS were superior for early CTC changes compared to PSA response endpoints, and similar to 6-month rPFS. Early CTC declines were good predictors of improved outcomes in mCRPC patients treated with docetaxel in this small study, offering a superior and/or earlier estimation of docetaxel benefit in comparison to PSA or rPFS that merits further confirmation in larger studies.

Circulating tumor cell

Progression-free survival

10.3390/cancers13102334

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Citations (13)

HSD3B1 (1245A>C) polymorphism and clinical outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone acetate (AA) and enzalutamide (ENZA): Results from two prospective studies.

Journal of Clinical Oncology (2020)

Isabel M. Aragón Daniel Khalaf Rebeca Lozano Matti Annala Sinja Taavitsainen

5525 Background: The common HSD3B1 (1245A > C) germline variant is associated with increased de-novo synthesis of androgens and worse outcomes in men treated with androgen-deprivation therapy in metastatic hormone sensitive prostate cancer. The aim of this study is to determine the role of this polymorphism on treatment outcomes for AA and ENZA in patients with mCRPC. Methods: A total of 547 patients treated with AA or ENZA for mCRPC from two prospective cohorts; cohort 1 included 202 from British Columbia (Canada) and cohort 2 enrolled 345 patients from the Spanish study PROREPAIR-B. HSD3B1 genotype was determined by targeted sequencing in cohort 1 and by Taqman SNP genotyping assay in cohort 2. Associations between HSD3B1 genotypes and (TTPP), time to progression (TTP) and overall survival (OS) were evaluated via univariate COX regression. Multivariate analysis was performed to determine the independent association of each covariate. Results: The proportions of patients with a homozygous wild-type HSD3B1 (AA), heterozygous (AC) and homozygous variant (CC) genotype were respectively 45.6%, 39.4% and 15%. As expected, known prognostic factors for mCRPC such as hemoglobin, alkaline phosphatase (ALP), LDH, PSA at baseline as well as site of metastasis were significantly associated with TTPP and TPP. In the combined cohort, HSD3B1 (CC) genotype was associated with worse TTP (HR 1.31, 95%CI 1.02-1.67, p = 0.032) and PSA response rates (48% for CC vs 62% and 65% for AA and AC, respectively (p = 0.019, χ²)). Similar trend was observed for TTPP (HR 1.28, 95%CI 0.99-1.66, p = 0.064). OS was not different among genotypes, but was significantly shorter for patients with CC genotype in cohort 1 (HR 1.97, 95%CI 1.14-3.40, p = 0.016). There was no association between HSD3B1 genotype and time to castration-resistance in either of the two cohorts. Multivariable analysis showed that LDH, ALP, hemoglobin and use of AA or ENZA as first-line therapy for mCRPC were independent prognostic factors for TTP and TTPP; non-significant association was observed for genotype and TTP. Conclusions: HSD3B1 homozygous variant genotype (CC) was associated with shorter TTP and lower PSA response rate in mCRPC patients treated with AA or ENZA. However, the CC genotype did not provide prognostic information beyond that conferred by standard clinical variables, suggesting that it may not be a suitable stand-alone biomarker in mCRPC.

Enzalutamide

Abiraterone acetate

10.1200/jco.2020.38.15_suppl.5525

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Pseudomonas savastanoi pv. savastanoi: some like it knot

Molecular Plant Pathology (2012)

Cayo Ramos Isabel Matas Leire Bardaji Isabel M. Aragón Jesús Murillo

Summary P seudomonas savastanoi pv . savastanoi is the causal agent of olive ( O lea europaea ) knot disease and an unorthodox member of the P . syringae complex, causing aerial tumours instead of the foliar necroses and cankers characteristic of most members of this complex. Olive knot is present wherever olive is grown; although losses are difficult to assess, it is assumed that olive knot is one of the most important diseases of the olive crop. The last century witnessed a large number of scientific articles describing the biology, epidemiology and control of this pathogen. However, most P . savastanoi pv. savastanoi strains are highly recalcitrant to genetic manipulation, which has effectively prevented the pathogen from benefitting from the scientific progress in molecular biology that has elevated the foliar pathogens of the P . syringae complex to supermodels. A number of studies in recent years have made significant advances in the biology, ecology and genetics of P . savastanoi pv. savastanoi , paving the way for the molecular dissection of its interaction with other nonpathogenic bacteria and their woody hosts. The selection of a genetically pliable model strain was soon followed by the development of rapid methods for virulence assessment with micropropagated olive plants and the analysis of cellular interactions with the plant host. The generation of a draft genome of strain NCPPB 3335 and the closed sequence of its three native plasmids has allowed for functional and comparative genomic analyses for the identification of its pathogenicity gene complement. This includes 34 putative type III effector genes and genomic regions, shared with other pathogens of woody hosts, which encode metabolic pathways associated with the degradation of lignin‐derived compounds. Now, the time is right to explore the molecular basis of the P . savastanoi pv. savastanoi –olive interaction and to obtain insights into why some pathovars like it necrotic and why some like it knot. Synonyms P seudomonas syringae pv. savastanoi . Taxonomy Kingdom Bacteria; Phylum Proteobacteria; Class G ammaproteobacteria ; Family P seudomonadaceae ; Genus P seudomonas ; included in genomospecies 2 together with at least P . amygdali , P . ficuserectae , P . meliae and 16 other pathovars from the P . syringae complex ( aesculi , ciccaronei , dendropanacis , eriobotryae , glycinea , hibisci , mellea , mori , myricae , phaseolicola , photiniae , sesami , tabaci , ulmi and certain strains of lachrymans and morsprunorum ); when a formal proposal is made for the unification of these bacteria, the species name P . amygdali would take priority over P . savastanoi . Microbiological properties Gram‐negative rods, 0.4–0.8 × 1.0–3.0 μ m, aerobic. Motile by one to four polar flagella, rather slow growing, optimal temperatures for growth of 25–30 ° C ; oxidase negative, arginine dihydrolase negative; elicits the hypersensitive response on tobacco; most isolates are fluorescent and levan negative, although some isolates are nonfluorescent and levan positive. Host range P . savastanoi pv. savastanoi causes tumours in cultivated and wild olive and ash ( F raxinus excelsior ). Although strains from olive have been reported to infect oleander ( N erium oleander ), this is generally not the case; however, strains of P . savastanoi pv. nerii can infect olive. Pathovars fraxini and nerii are differentiated from pathovar savastanoi mostly in their host range, and were not formally recognized until 1996. Literature before about 1996 generally names strains of the three pathovars as P . syringae ssp. savastanoi or P . savastanoi ssp. savastanoi , contributing to confusion on the host range and biological properties. Disease symptoms Symptoms of infected trees include hyperplastic growths (tumorous galls or knots) on the stems and branches of the host plant and, occasionally, on leaves and fruits. Epidemiology The pathogen can survive and multiply on aerial plant surfaces, as well as in knots, from where it can be dispersed by rain, wind, insects and human activities, entering the plant through wounds. Populations are very unevenly distributed in the plant, and suffer drastic fluctuations throughout the year, with maximum numbers of bacteria occurring during rainy and warm months. Populations of P . savastanoi pv. savastanoi are normally associated with nonpathogenic bacteria, both epiphytically and endophytically, and have been demonstrated to form mutualistic consortia with E rwinia toletana and P antoea agglomerans , which could result in increased bacterial populations and disease symptoms. Disease control Based on preventive measures, mostly sanitary and cultural practices. Integrated control programmes benefit from regular applications of copper formulations, which should be maintained for at least a few years for maximum benefit. Olive cultivars vary in their susceptibility to olive knot, but there are no known cultivars with full resistance to the pathogen. Useful websites http://www.pseudomonas‐syringae.org/ ; http://genome.ppws.vt.edu/cgi‐bin/MLST/home.pl ; ASAP access to the P . savastanoi pv. savastanoi NCPPB 3335 genome sequence https://asap.ahabs.wisc.edu/asap/logon.php .

Pseudomonas syringae

10.1111/j.1364-3703.2012.00816.x

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Citations (90)

Plasma kisspeptin levels are elevated in cord blood and present sexual dimorphism in the adult population: Relation with leptin, gonadotropins and anthropometrical data

Peptides (2011)

Jimena Pita Sandra Rado-Peralta Teresa Gavela‐Pérez Isabel M. Aragón Vicente Barrios

Sexual dimorphism

Kisspeptin

Cord blood

10.1016/j.peptides.2011.01.030

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