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Despite several improvements in outcomes, metastatic prostate cancer remains deadly. Alterations in the homologous recombination repair (HRR) pathway are associated with more aggressive disease. Olaparib and rucaparib, two poly-ADP-ribose polymerase (PARP) inhibitors, have received approval from the authorities of several countries for their anti-tumoral effects in patients with metastatic castration-resistant prostate cancers harboring HRR gene alterations, in particular BRCA2. More recently, it has been hypothesized that new hormonal therapies (NHTs) and PARP inhibitors (PARPi) could have synergistic actions and act independently of HRR deficiency. This review proposes to discuss the advantages and disadvantages of PARPi used as monotherapy or in combination with NHTs and whether there is a need for molecular selection.
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MADS transcription factors are master regulators of plant reproduction and flower development. The SEPALLATA (SEP) subfamily of MADS transcription factors is required for the development of floral organs and plays roles in inflorescence architecture and development of the floral meristem. SEPALLATAs act as organizers of MADS complexes, forming both heterodimers and heterotetramers in vitro. To date, the MADS complexes characterized in angiosperm floral organ development contain at least one SEPALLATA protein. Whether DNA-binding by SEPALLATA-containing dimeric MADS complexes is sufficient for launching floral organ identity programs, however, is not clear as only defects in floral meristem determinacy were observed in tetramerization--impaired SEPALLATA mutant proteins. Here, we used a combination of genome-wide binding studies, high resolution structural studies of the SEP3/AGAMOUS (AG) tetramerization domain, structure-based mutagenesis and complementation experiments in Arabidopsis (Arabidopsis thaliana) sep1 sep2 sep3 and sep1 sep2 sep3 ag-4 plants transformed with versions of SEP3 encoding tetramerization mutants. We demonstrate that while SEP3 heterodimers can bind DNA both in vitro and in vivo and recognize the majority of SEP3 wild-type binding sites genome-wide, tetramerization is required not only for floral meristem determinacy, but also for floral organ identity in the second, third and fourth whorls.
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INTRODUCTION: The increasing number of subjects with benign prostate obstruction (BPO) has become a worldwide concern. The sexual problem after benign prostate enlargement (BPE) surgery that has received the most attention in the literature is ejaculation disorder. However, there appears to be a change in orgasmic sensation independent of ejaculation retention. The objective of our study is to explore the influence of BPE surgery on orgasmic function. METHODS: We evaluated the prospective, multicenter clinical data of 104 patients undergoing BPE surgery who reported maintaining sexual activity from January 2016 to November 2020. The endpoint of this study was to decipher the percentage of patients with an orgasm disorder as assessed by the difference between pre-and-postoperative question 10 of the IIEF 15 questionnaire. RESULTS: Orgasm function was stable, improved, and degraded in 34% (n=35), 30% (n=31), and 36% (n=38) respectively. A deterioration in orgasm was statistically significant in men who maintained quality ejaculation with retained force preoperatively and a high IIEF15 scale values preoperative of orgasmic function, overall and intercourse patient satisfaction. CONCLUSION: To enable the patient to maintain a satisfying and healthy sex life after any BPE surgery, urologist physicians should know the prevalence of orgasmic side effects after surgical treatment to provide appropriate counseling to patients. LEVEL OF EVIDENCE: Grade 4.
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Orgasmo , Hiperplasia Prostática , Humanos , Masculino , Hiperplasia Prostática/cirugía , Persona de Mediana Edad , Estudios Prospectivos , Anciano , Prostatectomía/efectos adversos , Prostatectomía/métodos , Complicaciones Posoperatorias/etiología , Disfunciones Sexuales Fisiológicas/etiología , Satisfacción del PacienteRESUMEN
PURPOSE: To compare the outcomes of patients undergoing robotic YV plasty for bladder neck contracture (BNC) vs. vesico-urethral anastomotic stricture (VUAS). METHODS: A retrospective study included male patients who underwent robotic YV plasty for BNC after endoscopic treatment of BPH or VUAS between August 2019 and March 2023 at a single academic center. The primary assessed was the patency rate at 1 month post-YV plasty and during the last follow-up visit. RESULTS: A total of 21 patients were analyzed, comprising 6 in the VUAS group and 15 in the BNC group. Patients with VUAS had significantly longer operative times (277.5 vs. 146.7 min; p = 0.008) and hospital stay (3.2 vs. 1.7 days; p = 0.03). Postoperative complications were more common in the VUAS group (66.7% vs. 26.7%; p = 0.14). All patients resumed spontaneous voiding postoperatively. Five patients (23.8%) who developed de novo stress urinary incontinence had already an AUS (n = 1) or required concomitant AUS implantation (n = 3), all of whom were in the VUAS group (83.3% vs. 0%; p < 0.0001). The proportion of patients improved was similar in both groups (PGII = 1 or 2: 83.3% vs. 80%; p = 0.31). Stricture recurrence occurred in 9.5% of patients in the whole cohort, with no significant difference between the groups (p = 0.50). Long-term reoperation was required in three VUAS patients, showing a statistically significant difference between the groups (p = 0.05). CONCLUSION: Robotic YV plasty is feasible for both VUAS and BNC. While functional outcomes and stricture-free survival may be similar for both conditions, the perioperative outcomes were less favorable for VUAS patients.
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Contractura , Procedimientos Quirúrgicos Robotizados , Estrechez Uretral , Obstrucción del Cuello de la Vejiga Urinaria , Humanos , Masculino , Vejiga Urinaria/cirugía , Constricción Patológica/etiología , Constricción Patológica/cirugía , Procedimientos Quirúrgicos Robotizados/efectos adversos , Estudios Retrospectivos , Obstrucción del Cuello de la Vejiga Urinaria/cirugía , Obstrucción del Cuello de la Vejiga Urinaria/complicaciones , Contractura/cirugía , Estrechez Uretral/etiología , Estrechez Uretral/cirugía , Prostatectomía/efectos adversosRESUMEN
We report nationwide real-life practice in the management of prostate cancer (PC) in France in a population of 4936750 men. All prostate-specific antigen (PSA) blood tests performed between 2006 and 2018 were recorded in a National Health registry, which allowed to identify 692516 men diagnosed with PC and a control population consisting of 3899509 men without PC. PSA tests, age at diagnosis, treatments, and survival were analysed. Their management was analysed by age range and compared in the different French regions. Disparities were found in age at PSA testing and management approaches (surveillance, and local and systemic therapies). We found that 50% of men had received five PSA blood tests, but the first PSA test was taken late in life, with a peak in the decade between 65 and 75 yr of age. Adoption of monitoring was low (12%). Older men appeared to receive a late diagnosis with reduced chances of curative therapy and a subsequent increase in mortality, but cautious interpretation of our data is warranted in view of competing morbidities and other causes of death. The incidence of metastases at diagnosis, indicated by the use of systemic therapies, increased progressively from 2011 onwards. PATIENT SUMMARY: In this study, we report nationwide real-life practice in the management of prostate cancer (PC) in France in a population of 4936750 men, including 692516 patients with PC. We found that the first prostate-specific antigen test is taken too late in life, leading to a late diagnosis with reduced chances of curative therapy and a subsequent increase in mortality.
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Transcription factors (TFs) bind DNA at specific sequences to regulate gene expression. This universal process is achieved via their DNA-binding domain (DBD). In mammals, the vast diversity of DBD structural conformations and the way in which they contact DNA has been used to organize TFs in the TFClass hierarchical classification. However, the numerous DBD types present in plants but absent from mammalian genomes were missing from this classification. We reviewed DBD 3D structures and models available for plant TFs to classify most of the 56 recognized plant TF types within the TFClass framework. This extended classification adds eight new classes and 37 new families corresponding to DBD structures absent in mammals. Plant-TFClass provides a unique resource for TF comparison across families and organisms.
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Proteínas de Unión al ADN , Factores de Transcripción , Humanos , Animales , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas de Unión al ADN/genética , Mamíferos/genética , Mamíferos/metabolismo , ADN , Sitios de UniónRESUMEN
JASPAR (https://jaspar.elixir.no/) is a widely-used open-access database presenting manually curated high-quality and non-redundant DNA-binding profiles for transcription factors (TFs) across taxa. In this 10th release and 20th-anniversary update, the CORE collection has expanded with 329 new profiles. We updated three existing profiles and provided orthogonal support for 72 profiles from the previous release's UNVALIDATED collection. Altogether, the JASPAR 2024 update provides a 20% increase in CORE profiles from the previous release. A trimming algorithm enhanced profiles by removing low information content flanking base pairs, which were likely uninformative (within the capacity of the PFM models) for TFBS predictions and modelling TF-DNA interactions. This release includes enhanced metadata, featuring a refined classification for plant TFs' structural DNA-binding domains. The new JASPAR collections prompt updates to the genomic tracks of predicted TF binding sites (TFBSs) in 8 organisms, with human and mouse tracks available as native tracks in the UCSC Genome browser. All data are available through the JASPAR web interface and programmatically through its API and the updated Bioconductor and pyJASPAR packages. Finally, a new TFBS extraction tool enables users to retrieve predicted JASPAR TFBSs intersecting their genomic regions of interest.
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Bases de Datos Genéticas , Unión Proteica , Factores de Transcripción , Animales , Humanos , Ratones , Bases de Datos Genéticas/normas , Bases de Datos Genéticas/tendencias , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Plantas/genéticaRESUMEN
BACKGROUND: For non-muscle-invasive bladder cancer (NMIBC) requiring radical surgery, limited data are available comparing robotic-assisted radical cystectomy with intracorporeal urinary diversion (iRARC) to open radical cystectomy (ORC). The objective of this study was to compare the two surgical techniques. METHODS: A multicentric cohort of 593 patients with NMIBC undergoing iRARC or ORC between 2015 and 2020 was prospectively gathered. Perioperative and pathologic outcomes were compared. RESULTS: A total of 143 patients operated on via iRARC were matched to 143 ORC patients. Operative time was longer in the iRARC group (p = 0.034). Blood loss was higher in the ORC group (p < 0.001), with a consequent increased post-operative transfusion rate in the ORC group (p = 0.003). Length of stay was longer in the ORC group (p = 0.007). Post-operative complications did not differ significantly (all p > 0.05). DFS at 60 months was 55.9% in ORC and 75.2% in iRARC with a statistically significant difference (p = 0.033) found in the univariate analysis. CONCLUSION: We found that iRARC for patients with NMIBC is safe, associated with a lower blood loss, a lower transfusion rate and a shorter hospital stay compared to ORC. Complication rates were similar. No significant differences in survival analyses emerged across the two techniques.
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IMPORTANCE: SARS-CoV-2 is a new virus responsible for the Covid-19 pandemic. Although SARS-CoV-2 primarily affects the lungs, other organs are infected. Alterations of testosteronemia and spermatozoa motility in infected men have raised questions about testicular infection, along with high level in the testis of ACE2, the main receptor used by SARS-CoV-2 to enter host cells. Using an organotypic culture of human testis, we found that SARS-CoV-2 replicated with slow kinetics in the testis. The virus first targeted testosterone-producing Leydig cells and then germ-cell nursing Sertoli cells. After a peak followed by the upregulation of antiviral effectors, viral replication in the testis decreased and did not induce any major damage to the tissue. Altogether, our data show that SARS-CoV-2 replicates in the human testis to a limited extent and suggest that testicular damages in infected patients are more likely to result from systemic infection and inflammation than from viral replication in the testis.
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SARS-CoV-2 , Testículo , Replicación Viral , Humanos , Masculino , SARS-CoV-2/fisiología , Testículo/virología , Células Intersticiales del Testículo/virología , Células de Sertoli/virologíaRESUMEN
Radical prostatectomy (RP) can be performed using an open (ORP), laparoscopic (LRP) or robotic (RARP) approach. Most studies, even in experienced centers, have not provided solid evidence demonstrating better outcomes when using the robotic approach. In addition, one of the remaining concerns about RARP is its cost effectiveness, leading to no reimbursement for this surgical technique in some countries and thus health care inequality. We used data from a French national registry to improve knowledge of RP outcomes in a real-world scenario in order to guide and inform health care decision-makers. A total of 21 213 RP procedures were performed in 645 French centers in 2021 (ORP 20%, LRP 25%, and RARP 55% of cases). ORP was associated with longer hospital stay (p < 0.001), higher rates of postoperative complications (p < 0.001), fewer days out of hospital within 90 d of surgery (81.7 vs 83.6 vs 84.9 d for ORP vs LRP vs RARP; p < 0.00), and higher hospitalization costs (2424 vs 1789 vs 1302). RARP is an optimal and cost-effective approach, with several advantages over ORP. Our data can be used by health care decision-makers to facilitate access to and reimbursement for the robotic approach for RP indications. PATIENT SUMMARY: For men with prostate cancer for whom surgery is recommended, surgeons can remove the prostate using open surgery or a keyhole approach with or without robot assistance. Open surgery has higher costs, more complications, and longer hospital stays.
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The identification of genome-wide transcription factor binding sites (TFBS) is a critical step in deciphering gene and transcriptional regulatory networks. However, determining the genome-wide binding of specific TFs or TF complexes remains a technical challenge. DNA affinity purification sequencing (DAP-seq) and modifications such as sequential DAP-seq (seq-DAP-seq) are robust in vitro methods for mapping individual TF or TF complex binding sites in a genome-wide manner. DAP-seq protocols use a genomic DNA (gDNA) library from any target organism with or without amplification, allowing the determination of TF binding on naked or endogenously modified DNA, respectively. As a first step, the gDNA is fragmented to ~200 bp, end-repaired, and sequencing adaptors are added. This gDNA library can be used directly or an amplification step may be performed to remove DNA modifications such as cytosine methylation. DNA libraries are then incubated with an affinity-tagged TF or TF- complex immobilized on magnetic beads. The TF or TF complex of interest is generally produced using recombinant protein expression and purified prior to DNA affinity purification. After incubation of the DNA library with the immobilized TF of interest, multiple wash steps are performed to reduce non-specific DNA binding and the TF-DNA complexes eluted. The eluted DNA is PCR-amplified and sequenced using next-generation sequencing. The resulting sequence reads are mapped to the corresponding reference genome, identifying direct potential bound regions and binding sites of the TF or TF complex of interest. Predictive TFBS models are generated from the bound regions using downstream bioinformatics analysis pipelines. Here, we present a detailed protocol outlining the steps required for seq-DAP-seq of a heterooligomeric TF complex (Fig. 1) and briefly describe the downstream bioinformatics pipeline used to develop a robust TFBS model from sequencing data generated from a DAP-seq experiment.
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Regulación de la Expresión Génica , Factores de Transcripción , ADN de Plantas/genética , Factores de Transcripción/genética , Sitios de Unión , Análisis de Secuencia de ADNRESUMEN
Deep learning (DL), often called artificial intelligence (AI), has been increasingly used in Pathology thanks to the use of scanners to digitize slides which allow us to visualize them on monitors and process them with AI algorithms. Many articles have focused on DL applied to prostate cancer (PCa). This systematic review explains the DL applications and their performances for PCa in digital pathology. Article research was performed using PubMed and Embase to collect relevant articles. A Risk of Bias (RoB) was assessed with an adaptation of the QUADAS-2 tool. Out of the 77 included studies, eight focused on pre-processing tasks such as quality assessment or staining normalization. Most articles (n = 53) focused on diagnosis tasks like cancer detection or Gleason grading. Fifteen articles focused on prediction tasks, such as recurrence prediction or genomic correlations. Best performances were reached for cancer detection with an Area Under the Curve (AUC) up to 0.99 with algorithms already available for routine diagnosis. A few biases outlined by the RoB analysis are often found in these articles, such as the lack of external validation. This review was registered on PROSPERO under CRD42023418661.
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The order Parmales (class Bolidophyceae) is a minor group of pico-sized eukaryotic marine phytoplankton that contains species with cells surrounded by silica plates. Previous studies revealed that Parmales is a member of ochrophytes and sister to diatoms (phylum Bacillariophyta), the most successful phytoplankton group in the modern ocean. Therefore, parmalean genomes can serve as a reference to elucidate both the evolutionary events that differentiated these two lineages and the genomic basis for the ecological success of diatoms vs. the more cryptic lifestyle of parmaleans. Here, we compare the genomes of eight parmaleans and five diatoms to explore their physiological and evolutionary differences. Parmaleans are predicted to be phago-mixotrophs. By contrast, diatoms have lost genes related to phagocytosis, indicating the ecological specialization from phago-mixotrophy to photoautotrophy in their early evolution. Furthermore, diatoms show significant enrichment in gene sets involved in nutrient uptake and metabolism, including iron and silica, in comparison with parmaleans. Overall, our results suggest a strong evolutionary link between the loss of phago-mixotrophy and specialization to a silicified photoautotrophic life stage early in diatom evolution after diverging from the Parmales lineage.
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Diatomeas , Estramenopilos , Diatomeas/genética , Estramenopilos/genética , Fitoplancton/metabolismo , Genoma , Dióxido de SilicioRESUMEN
Background: Prostatic artery embolisation (PAE) is a minimally invasive treatment of symptomatic benign prostatic hyperplasia (BPH). Our aim was to compare patient's symptoms improvement after PAE and medical treatment. Methods: A randomised, open-label, superiority trial was set in 10 French hospitals. Patients with bothersome lower urinary tract symptoms (LUTS) defined by International Prostatic Symptom Score (IPSS) > 11 and quality of life (QoL) > 3, and BPH ≥50 ml resistant to alpha-blocker monotherapy were randomly assigned (1:1) to PAE or Combined Therapy ([CT], oral dutasteride 0.5 mg/tamsulosin hydrochloride 0.4 mg per day). Randomisation was stratified by centre, IPSS and prostate volume with a minimisation procedure. The primary outcome was the 9-month IPSS change. Primary and safety analysis were done according to the intention-to-treat (ITT) principle among patients with an evaluable primary outcome. ClinicalTrials.gov Identifier: NCT02869971. Findings: Ninety patients were randomised from September 2016 to February 2020, and 44 and 43 patients assessed for primary endpoint in PAE and CT groups, respectively. The 9-month change of IPSS was -10.0 (95% confidence interval [CI]: -11.8 to -8.3) and -5.7 (95% CI: -7.5 to -3.8) in the PAE and CT groups, respectively. This reduction was significantly greater in the PAE group than in the CT group (-4.4 [95% CI: -6.9 to -1.9], p = 0.0008). The IIEF-15 score change was 8.2 (95% CI: 2.9-13.5) and -2.8 (95% CI: -8.4 to 2.8) in the PAE and CT groups, respectively. No treatment-related AE or hospitalisation was noticed. After 9 months, 5 and 18 patients had invasive prostate re-treatment in the PAE and CT group, respectively. Interpretation: In patients with BPH ≥50 ml and bothersome LUTS resistant to alpha-blocker monotherapy, PAE provides more urinary and sexual symptoms benefit than CT up to 24 months. Funding: French Ministry of Health and a complementary grant from Merit Medical.
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PURPOSE: Using large French retrospective study cohort of chemotherapy-naïve metastatic castration-resistant prostate cancer patients (mCRPC; n = 10,308) comparing survival between patients who initiated abiraterone (ABI; 64%) and those initiating enzalutamide (ENZ; 36%), the present objective was to describe treatment patterns in the 2 years following initiation. METHOD: Using the national health data system (SNDS) from 2014 to 2018, we first explored the number of treatment lines, and secondly, patterns of patient management using state sequence analysis; cluster analyses were performed on the 0 to 12 month and 13 to 24 month periods. Age, Charlson score, and duration of androgen deprivation therapy (ADT) were obtained for each cluster in the first year of follow-up. RESULTS: Patients with only 1 treatment line accounted for 52%. In the 0 to 12 month sequence analysis, the main clusters among ABI/ENZ new users involved patients who continued the initial treatment (54% of 65% respectively) and discontinued active treatment (14.5% for both). Less than 2 years exposure to ADT prior to ABI/ENZ initiation was frequently observed for noncontrolled mCRPC, as shown in the death and switch from ABI/ENZ to docetaxel clusters. The clusters for a switch ABI/ENZ to ENZ/ABI involved 6% to 11% of the patients. CONCLUSION: Our study suggested fairly similar patterns between ABI and ENZ initiation. The cluster of patients with active treatment discontinuation needs to be further investigated, as well as factors influencing therapeutic choice. Better understanding for the use of second-generation hormone therapy in mCRPC in real life, could improve its implementation by clinicians in the early stages of prostate cancer.
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Neoplasias de la Próstata Resistentes a la Castración , Masculino , Humanos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología , Acetato de Abiraterona/uso terapéutico , Antagonistas de Andrógenos/uso terapéutico , Resultado del Tratamiento , Estudios Retrospectivos , NitrilosRESUMEN
In angiosperms, flower development requires the combined action of the transcription factor LEAFY (LFY) and the ubiquitin ligase adaptor F-box protein, UNUSUAL FLORAL ORGANS (UFO), but the molecular mechanism underlying this synergy has remained unknown. Here we show in transient assays and stable transgenic plants that the connection to ubiquitination pathways suggested by the UFO F-box domain is mostly dispensable. On the basis of biochemical and genome-wide studies, we establish that UFO instead acts by forming an active transcriptional complex with LFY at newly discovered regulatory elements. Structural characterization of the LFY-UFO-DNA complex by cryo-electron microscopy further demonstrates that UFO performs this function by directly interacting with both LFY and DNA. Finally, we propose that this complex might have a deep evolutionary origin, largely predating flowering plants. This work reveals a unique mechanism of an F-box protein directly modulating the DNA binding specificity of a master transcription factor.
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Proteínas de Arabidopsis , Arabidopsis , Proteínas F-Box , Factores de Transcripción/metabolismo , Proteínas de Arabidopsis/metabolismo , Arabidopsis/genética , Proteínas F-Box/metabolismo , Microscopía por Crioelectrón , Regulación de la Expresión Génica de las Plantas , Flores/genéticaRESUMEN
BACKGROUND: Intratumor heterogeneity (ITH) is a key feature in clear cell renal cell carcinomas (ccRCCs) that impacts outcomes such as aggressiveness, response to treatments, or recurrence. In particular, it may explain tumor relapse after surgery in clinically low-risk patients who did not benefit from adjuvant therapy. Recently, single-cell RNA sequencing (scRNA-seq) has emerged as a powerful tool to unravel expression ITH (eITH) and might enable better assessment of clinical outcomes in ccRCC. OBJECTIVE: To explore eITH in ccRCC with a focus on malignant cells (MCs) and assess its relevance to improve prognosis for low-risk patients. DESIGN, SETTING, AND PARTICIPANTS: We performed scRNA-seq on tumor samples from five untreated ccRCC patients ranging from pT1a to pT3b. Data were complemented with a published dataset composed of pairs of matched normal and ccRCC samples. INTERVENTION: Radical or partial nephrectomy on untreated ccRCC patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Viability and cell type proportions were determined by flow cytometry. Following scRNA-seq, a functional analysis was performed and tumor progression trajectories were inferred. A deconvolution approach was applied on an external cohort, and Kaplan-Meier survival curves were estimated with respect to the prevalence of malignant clusters. RESULTS AND LIMITATIONS: We analyzed 54 812 cells and identified 35 cell subpopulations. The eITH analysis revealed that each tumor contained various degrees of clonal diversity. The transcriptomic signatures of MCs in one particularly heterogeneous sample were used to design a deconvolution-based strategy that allowed the risk stratification of 310 low-risk ccRCC patients. CONCLUSIONS: We described eITH in ccRCCs, and used this information to establish significant cell population-based prognostic signatures and better discriminate ccRCC patients. This approach has the potential to improve the stratification of clinically low-risk patients and their therapeutic management. PATIENT SUMMARY: We sequenced the RNA content of individual cell subpopulations composed of clear cell renal cell carcinomas and identified specific malignant cells the genetic information of which can be used to predict tumor progression.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/cirugía , Carcinoma de Células Renales/patología , Neoplasias Renales/patología , Pronóstico , Estadificación de Neoplasias , Recurrencia Local de Neoplasia/patología , Biomarcadores , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisisRESUMEN
Testis tumors are uncommon in oncology, and testicular metastasis from distant solid tumors are even rarer. We present two cases encountered in our department of pathology in CHU de Rennes, France. Moreover, we collected all reported cases in the Medline/PubMed databases of non-hematopoietic secondary testis tumors in adults, excluding autopsy studies, to propose an integrative study on this topic. In total, we report 98 cases of secondary testis lesions to prostate (n=38, 38.77 %), colorectal (n=19, 19.39%), gastric (n=12, 12.24%), kidney (n=7, 7.14%), lung (n=6, 6.12%) and other primary cancers. The median age at diagnosis was 66.5 years. We identified significantly more prostate adenocarcinoma (P<0.0001) when the primary tumor was known and significantly more colorectal adenocarcinoma (P=0.035) and pancreatic adenocarcinoma (P=0.002) when the primary tumor was unknown. The age at diagnosis was older when the primary tumor was known (P=0.007). We present the challenges for the diagnosis and propose some elements for diagnosis orientation. Finally, we discuss the possible ways of metastatic dissemination from primary site to testis, as illustrated by the two cases we present.
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Adenocarcinoma , Neoplasias Colorrectales , Neoplasias Pancreáticas , Neoplasias Testiculares , Masculino , Adulto , Humanos , Anciano , Testículo/patología , Adenocarcinoma/patología , Neoplasias Pancreáticas/patología , Neoplasias Testiculares/diagnóstico , Neoplasias Testiculares/patología , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/patologíaRESUMEN
DNA methylation is an epigenetic mark that fine-tunes gene expression, notably by negatively or positively regulating transcription factor (TF)-DNA binding. In plants, DNA methylation has primarily been shown to inhibit TF-DNA binding. However, little is known about the underlying mechanisms. Here, we show that DNA methylation decreases the binding of several Arabidopsis (Arabidopsis thaliana) WRKY TFs to their genomic regions and their binding sites in vitro. We also provide evidence that DNA methylation at a single cytosine located in a functional core W-box motif repels DNA binding of AtWRKY40 in vitro. Using structural modelling, we further demonstrate that this cytosine interacts through van der Waals contacts with the conserved tyrosine of WRKY-DNA binding domains. Importantly, our model predicts steric hindrance when a 5-methyl group is present on this specific cytosine, thereby likely preventing tight binding of WRKY-DNA binding domains. Finally, because the WRKY motif and the residues involved in DNA contacts are conserved across Arabidopsis and rice (Oryza sativa) WRKY TFs, we propose that this methylation-dependent WRKY-DNA binding inhibitory mechanism could be widespread across plant species.