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PURPOSE: Our aim was to investigate the course of the hearing capacity of the better-hearing ear in single-sided deafness (SSD) and asymmetric hearing loss (AHL) over time, in a multicenter study. METHODS: We included 2086 pure-tone audiograms from 323 patients with SSD and AHL from four hospitals and 156 private practice otorhinolaryngologists. We collected: age, gender, etiology, duration of deafness, treatment with CI, number and monosyllabic speech recognition, numerical rating scale (NRS) of tinnitus intensity, and the tinnitus questionnaire according to Goebel and Hiller. We compared the pure tone audiogram of the better-hearing ear in patients with SSD with age- and gender-controlled hearing thresholds from ISO 7029:2017. RESULTS: First, individuals with SSD showed a significantly higher hearing threshold from 0.125 to 8 kHz in the better-hearing ear compared to the ISO 7029:2017. The duration of deafness of the poorer-hearing ear showed no relationship with the hearing threshold of the better-hearing ear. The hearing threshold was significantly higher in typically bilaterally presenting etiologies (chronic otitis media, otosclerosis, and congenital hearing loss), except for Menière's disease. Second, subjects that developed AHL did so in 5.19 ± 5.91 years and showed significant reduction in monosyllabic word and number recognition. CONCLUSIONS: Individuals with SSD show significantly poorer hearing in the better-hearing ear than individuals with NH from the ISO 7029:2017. In clinical practice, we should, therefore, inform our SSD patients that their disease is accompanied by a reduced hearing capacity on the contralateral side, especially in certain etiologies.
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Implantación Coclear , Implantes Cocleares , Sordera , Pérdida Auditiva Unilateral , Percepción del Habla , Acúfeno , Humanos , Acúfeno/cirugía , Pérdida Auditiva Unilateral/diagnóstico , Pérdida Auditiva Unilateral/etiología , Pérdida Auditiva Unilateral/cirugía , Audición , Sordera/cirugía , Pruebas AuditivasRESUMEN
BACKGROUND: Immune-mediated inflammatory diseases (IMID) can lead to a substantial disease burden for those affected, in particular by the concomitant occurrence of other IMIDs or in the presence of comorbidities. The care of patients with IMIDs is complex and involves various medical disciplines. OBJECTIVE: To describe the burden of disease and the current routine drug treatment of patients with IMID. MATERIAL AND METHODS: The retrospective cross-sectional analysis was based on statutory health insurance claims data from the InGef database. Prevalent patients with psoriasis (Pso), psoriatic arthritis (PsA), spondylarthritis (SpA), rheumatoid arthritis (RA), Crohn's disease (MC), ulcerative colitis (CU), or connective tissue disease were identified among 3,988,695 insured patients in 2018. The concomitant occurrence of different IMIDs and the extent to which patients with IMID are affected by other comorbidities compared to a reference population were investigated. The current routine drug treatment was described based on the use of predefined forms of treatment. RESULTS: In the database 188,440 patients with IMID (4.7%) were identified. Compared to the reference population the prevalence of comorbidities, such as depressive episodes and cardiovascular risk factors was higher in patients with IMID. For MC, CU, RA, and PsA disease-modifying antirheumatic drugs (DMARD) and classical systemic forms of treatment were used most commonly. In Pso, SpA, and connective tissue disease nonsteroidal anti-inflammatory drugs (NSAID) were the most frequently used treatment often in combination with other drugs. CONCLUSION: A considerable number of patients with IMIDs (16.9-27.5%) suffer from different diseases of the IMID group. They are frequently affected by accompanying illnesses and require interdisciplinary medical treatment.
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Artritis Psoriásica , Artritis Reumatoide , Psoriasis , Espondiloartritis , Humanos , Estudios Transversales , Estudios Retrospectivos , Espondiloartritis/terapia , Agentes InmunomoduladoresRESUMEN
Variant-specific loss of heterozygosity (LOH) analyses may be useful to classify BRCA1/2 germline variants of unknown significance (VUS). The sensitivity and specificity of this approach, however, remains unknown. We performed comparative next-generation sequencing analyses of the BRCA1/2 genes using blood-derived and tumour-derived DNA of 488 patients with ovarian cancer enrolled in the observational AGO-TR1 trial (NCT02222883). Overall, 94 pathogenic, 90 benign and 24 VUS were identified in the germline. A significantly increased variant fraction (VF) of a germline variant in the tumour indicates loss of the wild-type allele; a decreased VF indicates loss of the variant allele. We demonstrate that significantly increased VFs predict pathogenicity with high sensitivity (0.84, 95% CI 0.77 to 0.91), poor specificity (0.63, 95% CI 0.53 to 0.73) and poor positive predictive value (PPV; 0.71, 95% CI 0.62 to 0.79). Significantly decreased VFs predict benignity with low sensitivity (0.26, 95% CI 0.17 to 0.35), high specificity (1.0, 95% CI 0.96 to 1.00) and PPV (1.0, 95% CI 0.85 to 1.00). Variant classification based on significantly increased VFs results in an unacceptable proportion of false-positive results. A significantly decreased VF in the tumour may be exploited as a reliable predictor for benignity, with no false-negative result observed. When applying the latter approach, VUS identified in four patients can now be considered benign. Trial registration number NCT02222883.
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Neoplasias de la Mama , Neoplasias Ováricas , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Femenino , Genes BRCA1 , Predisposición Genética a la Enfermedad , Células Germinativas/patología , Mutación de Línea Germinal/genética , Humanos , Pérdida de Heterocigocidad/genética , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/genética , Neoplasias Ováricas/patologíaRESUMEN
BACKGROUND: The aim of the BSP090 project is the establishment of European Pharmacopoeia Chemical Reference Substances (CRSs) in combination with corresponding standard ELISA methods for quantification of major allergens in allergen products. Here, we present data of a Phl p 5-specific sandwich ELISA that proved suitable for the quantification of Phl p 5, one of the major Timothy grass (Phleum pratense) pollen allergens. METHODS: A Phl p 5-specific ELISA system was assessed with respect to accuracy, precision, inter-assay (within laboratory) and inter-laboratory variations, in a ring trial including 14 laboratories in Europe and the USA. Model samples containing recombinant Phl p 5a CRS as well as native grass pollen extracts were analysed. Each participant was instructed to perform at least one preliminary assay to familiarise with the protocol, followed by three independent assays. RESULTS: The candidate standard ELISA proved suitable to quantify recombinant and native Phl p 5 with satisfactory precision (93% of results within ±30% acceptance range). Inter-assay variation (max. GCV 24%) and especially inter-laboratory variation (max. GCV 13%) showed conclusive results. When assessing accuracy by means of recovery of recombinant spikes from a grass pollen extract matrix, similarly satisfactory spike recovery results were observed for the two spikes with higher concentrations (all within ±30% acceptance range), whereas recovery of the lowest concentration spike was slightly poorer with mean results of six laboratories exceeding acceptance range. CONCLUSIONS: Based on the collaborative study results, the assessed Phl p 5-specific immunoassay is appropriate to be proposed as European Pharmacopoeia standard method.
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Alérgenos , Polen , Alérgenos/química , Ensayo de Inmunoadsorción Enzimática , Humanos , Phleum/química , Proteínas de Plantas/química , Poaceae , Estándares de ReferenciaRESUMEN
BACKGROUND: Five SARS-CoV-2 variants are currently considered as variants of concern (VOC). Omicron was declared a VOC at the end of November 2021. Based on different diagnostic methods, the occurrence of Omicron was reported by 52 countries worldwide on December 7 2021. First notified by South Africa with alarming reports on increasing infection rates, this new variant was soon suspected to replace the currently pre-dominating Delta variant leading to further infection waves worldwide. METHODS: Using VOC PCR screening and Next Generation Sequencing (NGS) analysis of selected samples, we investigated the circulation of Omicron in the German federal state Bavaria. For this, we analyzed SARS-CoV-2 surveillance data from our laboratory generated from calendar week (CW) 01 to 49/2021. RESULTS: So far, we have detected 69 Omicron cases in our laboratory from CW 47-49/2021 using RT-qPCR followed by melting curve analysis. The first 16 cases were analyzed by NGS and all were confirmed as Omicron. CONCLUSION: Our data strongly support no circulation of the new Omicron variant before CW 47/2021.
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COVID-19 , SARS-CoV-2 , COVID-19/diagnóstico , COVID-19/epidemiología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Reacción en Cadena en Tiempo Real de la Polimerasa , SARS-CoV-2/genéticaRESUMEN
Covalent organic frameworks (COFs) display a unique combination of chemical tunability, structural diversity, high porosity, nanoscale regularity, and thermal stability. Recent efforts are directed at using such frameworks as tunable scaffolds for chemical reactions. In particular, COFs have emerged as viable platforms for mimicking natural photosynthesis. However, there is an indisputable need for efficient, stable, and economical alternatives for the traditional platinum-based cocatalysts for light-driven hydrogen evolution. Here, we present azide-functionalized chloro(pyridine)cobaloxime hydrogen-evolution cocatalysts immobilized on a hydrazone-based COF-42 backbone that show improved and prolonged photocatalytic activity with respect to equivalent physisorbed systems. Advanced solid-state NMR and quantum-chemical methods allow us to elucidate details of the improved photoreactivity and the structural composition of the involved active site. We found that a genuine interaction between the COF backbone and the cobaloxime facilitates recoordination of the cocatalyst during the photoreaction, thereby improving the reactivity and hindering degradation of the catalyst. The excellent stability and prolonged reactivity make the herein reported cobaloxime-tethered COF materials promising hydrogen evolution catalysts for future solar fuel technologies.
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BACKGROUND: For individuals with ovarian cancer (OC), therapy options mainly depend on BRCA1/2 germline status. What is the prevalence of deleterious somatic variants, that is, does genetic tumour testing identify subgroups of individuals who also might benefit from targeted therapy? METHODS: Paired analysis of tumour-derived versus blood-derived DNA to determine the prevalence of deleterious somatic variants in OC predisposition genes (ATM, BRCA1/2, BRIP1, MSH2/6, PALB2, RAD51C/D and TP53) and the PIK3CA and PTEN genes in individuals with OC (AGO-TR1 study, NCT02222883). Results were complemented by BRCA1, PALB2 and RAD51C promoter methylation analyses and stratified by histological subtype; 473 individuals were included. RESULTS: The combined analyses revealed that deleterious germline variants in established OC predisposition genes (all: 125/473, 26.4%; BRCA1/2: 97/473, 20.5%), deleterious somatic variants in established OC predisposition genes excluding TP53 (all: 39/473, 8.2%; BRCA1/2: 30/473, 6.3%) and promoter methylation (all: 67/473, 14.2%; BRCA1: 57/473, 12.1%; RAD51C: 10/473, 2.1%; PALB2: 0/473) were mutually exclusive, with a few exceptions. The same holds true for deleterious somatic PIK3CA and/or PTEN variants (33/473, 7.0%) found to be enriched in endometrioid and clear cell OC (16/35, 45.7%); 84.3 % of the deleterious single-nucleotide/indel germline variants in established OC predisposition genes showed significantly higher variant fractions (VFs) in the tumour-derived versus blood-derived DNA, indicating a loss of the wild-type alleles. CONCLUSION: Tumour sequencing of the BRCA1, BRCA2, PIK3CA and PTEN genes along with BRCA1 and RAD51C promoter methylation analyses identified large subgroups of germline mutation-negative individuals who may be addressed in interventional studies using PARP or PI3K/AKT/mTOR inhibitors. TRIAL REGISTRATION NUMBER: NCT02222883.
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Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Neoplasias Ováricas/genética , Eliminación de Secuencia , Proteína BRCA1 , Proteína BRCA2 , Biomarcadores de Tumor , Biología Computacional/métodos , Variaciones en el Número de Copia de ADN , Metilación de ADN , Femenino , Estudios de Asociación Genética/métodos , Pruebas Genéticas , Mutación de Línea Germinal , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/epidemiología , Prevalencia , Regiones Promotoras GenéticasAsunto(s)
Antígenos de Plantas , Betula , Alérgenos , Humanos , Extractos Vegetales , Proteínas de Plantas , PolenRESUMEN
Importance: Testing for homologous recombination deficiency is required for the optimal treatment of high-grade epithelial ovarian cancer. The search for accurate biomarkers is ongoing. Objective: To investigate whether progression-free survival (PFS) and overall survival (OS) of patients with high-grade epithelial ovarian cancer treated with maintenance olaparib or placebo differed between patients with a tumor BRCA-like genomic profile and patients without a tumor BRCA-like profile. Design, Setting, and Participants: This cohort study was a secondary analysis of the PAOLA-1 randomized clinical trial that compared olaparib plus bevacizumab with placebo plus bevacizumab as maintenance treatment in patients with advanced high-grade ovarian cancer after a good response to first-line platinum with taxane chemotherapy plus bevacizumab, irrespective of germline or tumor BRCA1/2 mutation status. All patients with available tumor DNA were included in the analysis. The current analysis tested for an interaction between BRCA-like status and olaparib treatment on survival outcomes. The original trial was conducted between July 2015 and September 2017; at the time of data extraction for analysis in March 2022, a median follow-up of 54.1 months (IQR, 28.5-62.2 months) and a total follow-up time of 21â¯711 months was available, with 336 PFS and 245 OS events. Exposures: Tumor homologous recombination deficiency was assessed using the BRCA-like copy number aberration profile classifier. Myriad MyChoice CDx was previously measured. The trial was randomized between the olaparib and bevacizumab and placebo plus bevacizumab groups. Main Outcomes and Measures: This secondary analysis assessed hazard ratios (HRs) of olaparib vs placebo among biomarker strata and tested for interaction between BRCA-like status and olaparib treatment on PFS and OS, using Cox proportional hazards regression. Results: A total of 469 patients (median age, 60 [range 26-80] years) were included in this study. The patient cohort consisted of women with International Federation of Gynaecology and Obstetrics stage III (76%) high-grade serous (95%) ovarian cancer who had no evaluable disease or complete remission at initial or interval debulking surgery (76%). Thirty-one percent of the tumor samples (n = 138) harbored a pathogenic BRCA mutation, and BRCA-like classification was performed for 442 patients. Patients with a BRCA-like tumor had a longer PFS after olaparib treatment than after placebo (36.4 vs 18.6 months; HR, 0.49; 95% CI, 0.37-0.65; P < .001). No association of olaparib with PFS was found in patients with a non-BRCA-like tumor (17.6 vs 16.6 months; HR, 1.02; 95% CI, 0.68-1.51; P = .93). The interaction was significant (P = .004), and HRs and P values (for interaction) were similar in the relevant subgroups, OS, and multivariable analyses. Conclusions and Relevance: In this secondary analysis of the PAOLA-1 randomized clinical trial, patients with a BRCA-like tumor, but not those with a non-BRCA-like tumor, had a significantly longer survival after olaparib plus bevacizumab treatment than placebo plus bevacizumab treatment. Thus, the BRCA1-like classifier could be used as a biomarker for olaparib plus bevacizumab as a maintenance treatment.
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Carcinoma , Neoplasias Ováricas , Ftalazinas , Piperazinas , Embarazo , Humanos , Femenino , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/genética , Bevacizumab/uso terapéutico , Proteína BRCA1/genética , Estudios de Cohortes , Proteína BRCA2/genética , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Genómica , BiomarcadoresRESUMEN
Background: Colorectal cancer (CRC) ranks as the third most prevalent cancer globally, highlighting the pressing need to address its development. Inflammation plays a crucial role in augmenting the risk of CRC and actively contributes to all stages of tumorigenesis. Consequently, targeting early inflammatory responses in the intestinal tract to restore homeostasis holds significant potential for preventing and treating CRC. Fibrinogen C domain-containing 1 (FIBCD1), a chitin-binding transmembrane protein predominantly found on human intestinal epithelial cells (IECs), has garnered attention in previous research for its ability to effectively suppress inflammatory responses and promote tissue homeostasis at mucosal barriers. Methods: In this study, we investigated the role of FIBCD1 in CRC development using transgenic mice that mimic human expression of FIBCD1 at the intestinal mucosal barrier. To model aspects of CRC, we employed the azoxymethane/dextran sodium sulfate (AOM/DSS) mouse model. Additionally, we examined the expression pattern of FIBCD1 in surgical specimens obtained from human CRC patients by immunohistochemical methods. By accessing public data repositories, we further evaluated FIBCD1 expression in colon adenocarcinoma and explored survival outcomes associated with FIBCD1 expression. Results: Here, we demonstrate that FIBCD1 substantially impacts CRC development by significantly reducing intestinal inflammation and suppressing colorectal tumorigenesis in mice. Furthermore, we identify a soluble variant of FIBCD1 that is significantly increased in feces during acute inflammation. Finally, we demonstrate increased expression of FIBCD1 by immunohistochemistry in human CRC specimens at more developed tumor stages. These results are further supported by bioinformatic analyses of publicly available repositories, indicating increased FIBCD1 expression in tumor tissues, where higher expression is associated with unfavorable prognosis. Conclusion: Collectively, these findings suggest that FIBCD1 influences early inflammatory responses in the AOM/DSS model, leading to a reduction in tumor size and burden. The increased expression of FIBCD1 in human CRC samples raises intriguing questions regarding its role in CRC, positioning it as a compelling candidate and novel molecular target for future research.
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PURPOSE: Cochlea implant surgery with proper positioning of the cochlear electrode can be challenging. Intraoperative real-time hybrid laser-fluoroscopic-guided navigation based on a multiplanar cone beam computed tomography (CBCT) dataset opens up the opportunity to immediate radiological control of primary electrode misalignments and offering new insights into the cochlea electrode insertion routes and favorable cochlear implant-insertion angle. METHODS: In this retrospective study, 50 cases (29 males, 18 females) of conventional electrode implantation (without intraoperative image control; group A) and nine cases (7 males, 2 females) of CBCT-laser-fluoroscopic-guided surgery (group B) were included in the present study. CBCT-laser-guided surgery under real-time fluoroscopic control was conducted using an intraoperative C-arm CBCT. All patients received preoperative cross-sectional imaging (CT and MRI), in which cochlear malformation could be excluded. Postoperatively, we looked for electrode misplacements. RESULTS: In group A, electrode misalignment was detected postoperatively in 14 of 50 cases (28.0%). In group B, primary electrode misalignment was detected intraoperatively in two patients (22.2%). In both patients, the misalignments were corrected in the same session. The comparison of cochlear insertion angles showed significant differences. Group A: 47.5 ± 2.6° (actual conventional surgery) vs 17.6 ± 2.8° (theoretical CBCT-laser-fluoroscopic-guided surgery) P < 0.001. Group A vs group B: 47.5 ± 2.6° (actual conventional surgery; Group A) vs 17.9 ± 2.5° (actual CBCT-laser-fluoroscopic-guided surgery; Group B) P < 0.001. CONCLUSION: We consider that an intraoperative hybrid CBCT-laser-fluoroscopic-controlled approach in cochlear implant surgery using a C-arm CT can be beneficial, because electrode misalignments can be reduced and if it does occur, remedied in the same surgical session.
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Implantación Coclear , Implantes Cocleares , Cóclea/cirugía , Implantación Coclear/métodos , Tomografía Computarizada de Haz Cónico/métodos , Femenino , Humanos , Rayos Láser , Masculino , Estudios RetrospectivosRESUMEN
PURPOSE: Postoperative imaging following cochlear implant (CI) placement is currently the only means of diagnosing proper electrode position. Manual multiplanar reconstruction (MPR) analysis of CT and CBCT is time-consuming and requires extensive training. This study aims to evaluate the rate of CI misalignment and to determine the amount of time necessary to reach a diagnosis of correct versus incorrect CI placement for readers of different experience levels, using a novel algorithm for image analysis (ACIR) compared to MPR analysis. METHOD: The retrospective single centre study included 333 patients with cochlear implant surgery between May 2002 and May 2021. Postoperative CT and CBCT images were evaluated in three subgroups and the time to diagnosis was documented. Group 1: image evaluation using conventional MPR analysis; group 2: image evaluation by an experienced neuroradiologist via a novel ultra-fast algorithm; group 3: image evaluation by a young specialist via novel ultra-fast algorithm. T-test and Pearson's chi-squared test were used for inter-group comparisons. RESULTS: 333 patients (63.3 ± 15.9 years; 188 men) with 335 CIs were evaluated. The rate of CI misalignment diagnosed from 3D imaging was 14.3% (n = 48). MPR analysis required 255.7 ± 70.4 s per temporal bone, whereas Slicer plugin reduced analysis time to 83.3 ± 7.7 s (p < 0.001) for the experienced reader and 89.6 ± 8.7 s for the young specialist (p < 0.001). CONCLUSION: 3D postoperative imaging reveals high incidences of CI misalignment. Application of a novel ultra-fast algorithm significantly reduces the time for diagnosis compared to MPR analysis for readers of varying experience levels.
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Implantación Coclear , Implantes Cocleares , Algoritmos , Cóclea , Implantación Coclear/métodos , Humanos , Masculino , Estudios RetrospectivosRESUMEN
Cochlear implants (CIs) are the primary treatment method in patients with profound sensorineural hearing loss. Interpretation of postoperative imaging with conventional energy-integrating detector computed tomography (EID-CT) following CI surgery remains challenging due to metal artifacts. Still, the photon-counting detector (PCD-CT) is a new emerging technology with the potential to eliminate these problems. This study evaluated the performance of virtual monoenergetic (VME) EID-CT images versus PCD-CT in CI imaging. In this cadaveric study, two temporal bone specimens with implanted CIs were scanned with EID-CT and PCD-CT. The images were assessed according to the visibility of interelectrode wire, size of electrode contact, and diameter of halo artifacts. The visibility of interelectrode wire sections was significantly higher when reviewing PCD-CT images. The difference in diameter measurements for electrode contacts between the two CT scanner modalities showed that the PCD-CT technology generally led to significantly larger diameter readings. The larger measurements were closer to the manufacturer's specifications for the CI electrode. The size of halo artifacts surrounding the electrode contacts did not differ significantly between the two imaging modalities. PCT-CT imaging is a promising technology for CI imaging with improved spatial resolution and better visibility of small structures than conventional EID-CT.
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Implantes Cocleares , Humanos , Fantasmas de Imagen , Fotones , Tomógrafos Computarizados por Rayos X , Tomografía Computarizada por Rayos X/métodosRESUMEN
Mesenchymal stromal cells (MSC) increasingly emerge as an option to ameliorate non-alcoholic steatohepatitis (NASH), a serious disease, which untreated may progress to liver cirrhosis and cancer. Before clinical translation, the mode of action of MSC needs to be established. Here, we established NASH in an immune-deficient mouse model by feeding a high fat diet. Human bone-marrow-derived MSC were delivered to the liver via intrasplenic transplantation. As verified by biochemical and image analyses, human mesenchymal stromal cells improved high-fat-diet-induced NASH in the mouse liver by decreasing hepatic lipid content and inflammation, as well as by restoring tissue homeostasis. MSC-mediated changes in gene expression indicated the switch from lipid storage to lipid utilization. It was obvious that host mouse hepatocytes harbored human mitochondria. Thus, it is feasible that resolution of NASH in mouse livers involved the donation of human mitochondria to the mouse hepatocytes. Therefore, human MSC might provide oxidative capacity for lipid breakdown followed by restoration of metabolic and tissue homeostasis.
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Células Madre Mesenquimatosas , Enfermedad del Hígado Graso no Alcohólico , Animales , Dieta Alta en Grasa/efectos adversos , Humanos , Lípidos , Células Madre Mesenquimatosas/metabolismo , Ratones , Mitocondrias/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismoRESUMEN
BACKGROUND: Cancer patients are at risk of secondary therapy-related myeloid neoplasms (t-MNs). Acquired blood-specific mutations in clonal hematopoiesis (CH)-associated genes are t-MN risk factors, and their occurrence associated with cancer therapy and age. Patients with ovarian cancer (OC) showed a particularly high prevalence of CH-associated gene mutations, which may additionally be explained by the high proportion of a hereditary disease cause in this cancer entity. METHODS: We performed a retrospective analysis of 448 OC patients enrolled in the AGO-TR1 study; 249 were enrolled at primary diagnosis and 199 at platinum-sensitive recurrence. Analyses included the most frequently altered CH-associated genes (ASXL1, DNMT3A, GNAS, JAK2, PPM1D, SF3B1, SH2B3, SRSF2, TET2, TP53). Results were analyzed according to the BRCA1/2 germline (gBRCA1/2) mutation status. All statistical tests were 2-sided. RESULTS: Advanced age at blood draw and a high number of prior platinum-based chemotherapy lines were risk factors to acquire CH-associated gene mutations, with gene-specific effects observed. Binomial logistic regression suggested increased probabilities for gBRCA1/2 mutation carriers to acquire CH-associated PPM1D and TP53 gene mutations (PPM1D: odds ratio = 4.30, 95% confidence interval = 1.48 to 12.46, P = .007; TP53: odds ratio = 6.20, 95% confidence interval = 0.98 to 53.9, P = .06). This observation was due to a statistically significantly increased number of platinum-based chemotherapy lines in gBRCA1/2 mutation carriers vs noncarriers (PPM1D: mean [SD] = 2.04 [1.27] vs 1.04 [0.99], P < .001; TP53: mean [SD] = 2.83 [1.33] vs 1.07 [1.01], P < .001). No interaction between platinum-based chemotherapy and gBRCA1/2 mutation status with the occurrence of CH-associated gene mutations was observed. CONCLUSIONS: A positive gBRCA1/2 mutation status is not a risk factor to acquire CH-associated gene mutations. OC patients may benefit from monitoring CH-associated gene mutations, especially following carboplatin exposure. Future clinical studies are required to assess whether treatment regimen should be adapted according to individual t-MN risks.
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Hematopoyesis Clonal , Neoplasias Ováricas , Carcinoma Epitelial de Ovario , Humanos , Mutación , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Estudios RetrospectivosRESUMEN
Activation of the 5-lipoxygenase (5-LO) pathway leads to the biosynthesis of proinflammatory leukotriene lipid mediators. Genetic studies have associated 5-LO and its accessory protein, 5-LO-activating protein, with cardiovascular disease, myocardial infarction and stroke. Here we show that 5-LO-positive macrophages localize to the adventitia of diseased mouse and human arteries in areas of neoangiogenesis and that these cells constitute a main component of aortic aneurysms induced by an atherogenic diet containing cholate in mice deficient in apolipoprotein E. 5-LO deficiency markedly attenuates the formation of these aneurysms and is associated with reduced matrix metalloproteinase-2 activity and diminished plasma macrophage inflammatory protein-1alpha (MIP-1alpha; also called CCL3), but only minimally affects the formation of lipid-rich lesions. The leukotriene LTD(4) strongly stimulates expression of MIP-1alpha in macrophages and MIP-2 (also called CXCL2) in endothelial cells. These data link the 5-LO pathway to hyperlipidemia-dependent inflammation of the arterial wall and to pathogenesis of aortic aneurysms through a potential chemokine intermediary route.
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Aneurisma de la Aorta Abdominal/etiología , Araquidonato 5-Lipooxigenasa/metabolismo , Regulación de la Expresión Génica , Hiperlipidemias/complicaciones , Leucotrienos/biosíntesis , Macrófagos/metabolismo , Proteínas Activadoras de la 5-Lipooxigenasa , Análisis de Varianza , Animales , Western Blotting , Proteínas Portadoras/metabolismo , Quimiocina CCL2/sangre , Quimiocina CCL3 , Quimiocina CCL4 , Quimiocina CXCL1 , Quimiocinas CXC/metabolismo , Colatos , Tejido Conectivo/metabolismo , Citocinas/sangre , Cartilla de ADN , Dieta Aterogénica , Técnicas Histológicas , Humanos , Inmunohistoquímica , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Leucotrieno D4/metabolismo , Proteínas Inflamatorias de Macrófagos/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Neovascularización Patológica/metabolismo , ARN/genética , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
The identification of germline copy number variants (CNVs) by targeted next-generation sequencing (NGS) frequently relies on in silico CNV prediction tools with unknown sensitivities. We investigated the performances of four in silico CNV prediction tools, including one commercial (Sophia Genetics DDM) and three non-commercial tools (ExomeDepth, GATK gCNV, panelcn.MOPS) in 17 cancer predisposition genes in 4208 female index patients with familial breast and/or ovarian cancer (BC/OC). CNV predictions were verified via multiplex ligation-dependent probe amplification. We identified 77 CNVs in 76 out of 4208 patients (1.81%); 33 CNVs were identified in genes other than BRCA1/2, mostly in ATM, CHEK2, and RAD51C and less frequently in BARD1, MLH1, MSH2, PALB2, PMS2, RAD51D, and TP53. The Sophia Genetics DDM software showed the highest sensitivity; six CNVs were missed by at least one of the non-commercial tools. The positive predictive values ranged from 5.9% (74/1249) for panelcn.MOPS to 79.1% (72/91) for ExomeDepth. Verification of in silico predicted CNVs is required due to high frequencies of false positive predictions, particularly affecting target regions at the extremes of the GC content or target length distributions. CNV detection should not be restricted to BRCA1/2 due to the relevant proportion of CNVs in further BC/OC predisposition genes.
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PURPOSE: Previously, we developed breast cancer BRCA1-like and BRCA2-like copy-number profile shrunken centroid classifiers predictive for mutation status and response to therapy, targeting homologous recombination deficiency (HRD). Therefore, we investigated BRCA1- and BRCA2-like classification in ovarian cancer, aiming to acquire classifiers with similar properties as those in breast cancer.Experimental Design: We analyzed DNA copy-number profiles of germline BRCA1- and BRCA2-mutant ovarian cancers and control tumors and observed that existing breast cancer classifiers did not sufficiently predict mutation status. Hence, we trained new shrunken centroid classifiers on this set and validated them in the independent The Cancer Genome Atlas dataset. Subsequently, we assessed BRCA1/2-like classification and obtained germline and tumor mutation and methylation status of cancer predisposition genes, among them several involved in HR repair, of 300 ovarian cancer samples derived from the consecutive cohort trial AGO-TR1 (NCT02222883). RESULTS: The detection rate of the BRCA1-like classifier for BRCA1 mutations and promoter hypermethylation was 95.6%. The BRCA2-like classifier performed less accurately, likely due to a smaller training set. Furthermore, three quarters of the BRCA1/2-like tumors could be explained by (epi)genetic alterations in BRCA1/2, germline RAD51C mutations and alterations in other genes involved in HR. Around half of the non-BRCA-mutated ovarian cancer cases displayed a BRCA-like phenotype. CONCLUSIONS: The newly trained classifiers detected most BRCA-mutated and methylated cancers and all tumors harboring a RAD51C germline mutations. Beyond that, we found an additional substantial proportion of ovarian cancers to be BRCA-like.
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Neoplasias de la Mama , Neoplasias Ováricas , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama/genética , Femenino , Genes BRCA2 , Mutación de Línea Germinal , Recombinación Homóloga , Humanos , Mutación , Neoplasias Ováricas/genética , Neoplasias Ováricas/patologíaRESUMEN
AIM: Although donorship issues and the integration of the new organs are the most distinguishing aspects of lung transplantation (LTx) compared to other kinds of 'high-tech' medicine, there is a paucity of papers on that matter. Therefore, we aimed to evaluate these aspects in young adult LTx recipients with at least 1-year survival. METHODS: Semi-structured interviews; content analysis of specific parts of the interviews; frequency distributions of resulting categories. SAMPLE: Forty-five adults aged 18-42 years (mean: 32 +/- 5.5 years). Post-transplant survival ranged from 1 to 11 years. RESULTS: The majority of recipients (60%) fulfilled criteria of denial towards the foreign organ and/or the donor. However, they were rather sensitive towards the ethical and psychological impact of the upcoming option of living donorship in LTx. Also, the majority of recipients (79%) understood that there might as well be good reason not to opt for a LTx. CONCLUSIONS: LTx recipients appeared at first sight 'pragmatic' towards the gift of life, but they remained sensitive to its ethical and psychological challenges.