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The drug efflux transporter P-glycoprotein, encoded by the ABCB1 gene, promotes acquired chemoresistance. We explored the presence and clinical relevance of circulating cell-free ABCB1 transcripts (cfABCB1tx) in ovarian cancer patients (173 longitudinal serum samples from 79 cancer patients) using digital droplet PCR. cfABCB1tx were readily detectable at primary diagnosis (median 354 mRNA copies/20 µl serum), paralleled FIGO-stage and predicted surgical outcome (p = 0.023, p=0.022, respectively). Increased cfABCB1tx levels at primary diagnosis indicated poor PFS (HR = 2.329, 95%CI:1.374-3.947, p = 0.0017) and OS (HR = 2.074, 95%CI:1.194-3.601, p = 0.0096). cfABCB1tx induction under platinum-based chemotherapy was an independent predictor for poor OS (HR = 2.597, 95%CI: 1.218-5.538, p = 0.013) and paralelled a micrometastatic phenotype, shaped by the presence of disseminated tumor cells in the bone marrow. A strong correlation was observed between cfABCB1tx and circulating transcripts of the metastasis-inducer MACC1, which is the transcriptional activator of ABCB1. Combined assessment of cfABCB1tx and circulating cell-free MACC1 transcripts (cfMACC1tx) resulted in an improved prognostic prediction, with the cfABCB1tx-high/cfMACC1tx-high phenotype bearing the highest risk for relapse and death. Conclusively, we provide proof of principle, that ABCB1 transcripts are readily traceable in the liquid-biopsy of ovarian cancer patients, advancing a new dimension for systemic monitoring of ABCB1/P-glycoprotein expression dynamics.
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Subfamília B de Transportador de Cassetes de Ligação de ATP , Neoplasias Ósseas , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/sangue , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Prognóstico , Neoplasias Ósseas/secundário , Neoplasias Ósseas/genética , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/patologia , Pessoa de Meia-Idade , Idoso , Biomarcadores Tumorais/genética , Fenótipo , Adulto , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Platina/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Estadiamento de Neoplasias , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
BACKGROUND AND AIMS: This study sought to determine the value of patient-derived organoids (PDOs) from esophago-gastric adenocarcinoma (EGC) for response prediction to neoadjuvant chemotherapy (neoCTx). METHODS: Endoscopic biopsies of patients with locally advanced EGC (n = 120) were taken into culture and PDOs expanded. PDOs' response towards the single substances of the FLOT regimen and the combination treatment were correlated to patients' pathological response using tumor regression grading. A classifier based on FLOT response of PDOs was established in an exploratory cohort (n = 13) and subsequently confirmed in an independent validation cohort (n = 13). RESULTS: EGC PDOs reflected patients' diverse responses to single chemotherapeutics and the combination regimen FLOT. In the exploratory cohort, PDOs response to single 5-FU and FLOT combination treatment correlated with the patients' pathological response (5-FU: Kendall's τ = 0.411, P = 0.001; FLOT: Kendall's τ = 0.694, P = 2.541e-08). For FLOT testing, a high diagnostic precision in receiver operating characteristic (ROC) analysis was reached with an AUCROC of 0.994 (CI 0.980 to 1.000). The discriminative ability of PDO-based FLOT testing allowed the definition of a threshold, which classified in an independent validation cohort FLOT responders from non-responders with high sensitivity (90%), specificity (100%) and accuracy (92%). CONCLUSION: In vitro drug testing of EGC PDOs has a high predictive accuracy in classifying patients' histological response to neoadjuvant FLOT treatment. Taking into account the high rate of successful PDO expansion from biopsies, the definition of a threshold that allows treatment stratification paves the way for an interventional trial exploring PDO-guided treatment of EGC patients.
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Adenocarcinoma , Carbamatos , Pirazinas , Piridinas , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamento farmacológico , Terapia Combinada , Terapia Neoadjuvante , Adenocarcinoma/tratamento farmacológico , Organoides , Fluoruracila/farmacologiaRESUMO
PURPOSE: To compare the results of retinal venous pressure (RVP) measurement performed with contact lens dynamometry (CLD) and with the new IOPstim. METHODS: In this cross-sectional study, we included 36 patients with primary open angle glaucoma with a median age (Q25; Q75) of 74 (64; 77) years (m/f = 18/18), baseline intraocular pressure (IOP): 13.9 (12.2; 15.1) mmHg. Median mean defect: - 5.8 (- 11.9; - 2.6) db. Principle of the IOPstim: an empty balloon with a diameter of 8 mm is positioned on the eye, laterally of the limbus. Under observation of the central retinal vein (CRV), the examiner inflates the balloon. As soon as the CRV starts pulsation, the inflation is stopped and the IOP is measured, equaling the RVP at this moment. In the CLD, the pulsation of the CRV is observed with a contact lens. The RVP is calculated from the attachment force applied when pulsation appears. COURSE OF EXAMINATIONS: Three single measurements of RVP in quick succession with both methods. The sequence of the two methods was randomized. The means of the three RVP measurements were compared. RESULTS: Pressures in mmHg. RVP: IOPstim: 19.4 ± 5.4 (mean ± SD), CLD: 20.3 ± 5.9. Range of three single measurements: IOPstim: 2.9 ± 1.5, CLD: 2.2 ± 1.1. The differences were RVPIOPstim - RVPCLD = - 0.94 ± 1.15, and approximately normally distributed. Bland-Altman analysis: only one data point was 0.5 mmHg higher than the upper line of agreement. The confidence interval of this line was 0.65 mmHg. Concordance correlation coefficient according to Lin (CCC): 0.96. Intraclass correlation coefficient: both methods, 0.94. CONCLUSION: In both methods, the range of the single measurements may be taken as a sign of good reliability, the CCC of 0.96 as a sign of a very good agreement. At the mean, the IOPstim RVP values were 1 mmHg lower than those obtained with the CLD. This difference may be due to the different directions of the prevailing force vectors induced by the instruments. The IOPstim seems applicable in glaucoma diagnostics.
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Glaucoma de Ângulo Aberto , Humanos , Glaucoma de Ângulo Aberto/diagnóstico , Estudos Transversais , Reprodutibilidade dos Testes , Pressão Venosa , Pressão Intraocular , Tonometria OcularRESUMO
PURPOSE: The effects of SARS-CoV-2 infections on the outcome of assisted reproduction techniques (ART) were studied in a retrospective cohort study. METHODS: The outcome of 1581 treatment cycles with embryo transfer at a university fertility center in Germany was compared in years before and during the COVID-19 pandemic. For 335 treatment cycles in 2022 a detailed analysis was carried out depending on infection and immunization status of both partners. RESULTS: ART cycles did not differ in most of the parameters examined between 2018-2022. In spite of comparable clinical pregnancy rates, there was a significantly higher miscarriage rate at 34.6% (27/78) in 2022, compared to 19.7% (29/147) in the pre-pandemic years of 2018-2019 (p = 0.014). In 37.0% of the treatment cycles (124/335) 2022 at least one partner reported a SARS-CoV-2-Infection 6 months before ART, mostly with the virus variant Omicron. Clinical pregnancy rates were lower in cycles without infection. Comparing women with confirmed infection to no infection, a significantly higher risk of miscarriage was seen (62.5% vs. 26.2%, p = 0.009). In treatment cycles of partners with basic immunization against SARS-CoV-2 a statistically significant increase of pregnancy rates was seen comparing to cycles with both unvaccinated partners (p = 0.011). CONCLUSION: The results indicate a negative impact of SARS-CoV-2-infections up to 6 months on ART treatment, in particular an increased risk of miscarriage. Vaccination was associated with a better outcome of ART treatment.
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Aborto Espontâneo , COVID-19 , Gravidez , Feminino , Humanos , Aborto Espontâneo/epidemiologia , SARS-CoV-2 , Estudos Retrospectivos , Pandemias , COVID-19/complicaçõesRESUMO
BACKGROUND: Girls and women are more frequently affected by headache than boys and men. The influence of gender on the effectiveness of headache therapies has so far been hardly investigated. We examined gender differences in the outpatient multimodal Dresden Child and Adolescent Headache Program DreKiP. METHODS: We treated 140 patients with primary headache in a 15-hour structured group program. At baseline (T0) and six (T1) and twelve months (T2) after the end of the program, data on headache-related limitation of daily activities (PedMIDAS) as well as headache frequency, intensity, and pain-related disability (P-PDI) were collected. Retrospectively, these data were analyzed separately for girls and boys. RESULTS: For 91 patients (9-19 years, medianâ¯= 15; 71.4â¯% female) data were available for at least two measurement time points. Girls showed significantly higher headache frequency than boys at all time points (median headache days/last three months at T0: â 43, â 20; T1: â 32, â 12; T2: â 28, â 9) as well as numerically higher headache-related limitation of daily life. There were significant effects over time with a decrease in headache frequency (F (2.88)â¯= 5.862; pâ¯= 0.004) and improvement in daily functioning (F (2.92)â¯= 5.340; pâ¯= 0.006). There was no gender-specific treatment response. DISCUSSION: The DreKiP therapy shows effects in girls and boys with primary headache. Higher headache frequencies and everyday life restrictions in girls may have hormonal but also psychosocial causes and should be addressed in educational measures.
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Cefaleia , Dor , Masculino , Criança , Humanos , Feminino , Adolescente , Estudos Retrospectivos , Cefaleia/terapiaRESUMO
EGFR exon 20 (EGFR Ex20) insertion mutations in non-small cell lung cancer (NSCLC) are insensitive to traditional EGFR tyrosine kinase inhibitors (TKIs). Mobocertinib is the only approved TKI specifically designed to target EGFR Ex20. We performed an international, real-world safety and efficacy analysis on patients with EGFR Ex20-positive NSCLC enrolled in a mobocertinib early access program. We explored the mechanisms of resistance by analyzing postprogression biopsies, as well as cross-resistance to amivantamab. Data from 86 patients with a median age of 67 years and a median of two prior lines of treatment were analyzed. Treatment-related adverse events (TRAEs) occurred in 95% of patients. Grade ≥3 TRAEs were reported in 38% of patients and included diarrhea (22%) and rash (8%). In 17% of patients, therapy was permanently discontinued, and two patients died due to TRAEs. Women were seven times more likely to discontinue treatment than men. In the overall cohort, the objective response rate to mobocertinib was 34% (95% CI, 24-45). The response rate in treatment-naïve patients was 27% (95% CI, 8-58). The median progression-free and overall survival was 5 months (95% CI, 3.5-6.5) and 12 months (95% CI, 6.8-17.2), respectively. The intracranial response rate was limited (13%), and one-third of disease progression cases involved the brain. Mobocertinib also showed antitumor activity following EGFR Ex20-specific therapy and vice versa. Potential mechanisms of resistance to mobocertinib included amplifications in MET, PIK3CA, and NRAS. Mobocertinib demonstrated meaningful efficacy in a real-world setting but was associated with considerable gastrointestinal and cutaneous toxicity.
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Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas , Indóis , Neoplasias Pulmonares , Pirimidinas , Masculino , Humanos , Feminino , Idoso , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Receptores ErbB/genética , ÉxonsRESUMO
Drug combination therapies for cancer treatment show high efficacy but often induce severe side effects, resulting in dose or cycle number reduction. We investigated the impact of neoadjuvant chemotherapy (neoCTx) adaptions on treatment outcome in 59 patients with pancreatic ductal adenocarcinoma (PDAC). Resections with tumor-free margins were significantly more frequent when full-dose neoCTx was applied. We determined if patient-derived organoids (PDOs) can be used to personalize poly-chemotherapy regimens by pharmacotyping of treatment-naïve and post-neoCTx PDAC PDOs. Five out of ten CTx-naïve PDO lines exhibited a differential response to either the FOLFIRINOX or the Gem/Pac regimen. NeoCTx PDOs showed a poor response to the neoadjuvant regimen that had been administered to the respective patient in 30% of cases. No significant difference in PDO response was noted when comparing modified treatments in which the least effective single drug was removed from the complete regimen. Drug testing of CTx-naïve PDAC PDOs and neoCTx PDOs may be useful to guide neoadjuvant and adjuvant regimen selection, respectively. Personalizing poly-chemotherapy regimens by omitting substances with low efficacy could potentially result in less severe side effects, thereby increasing the fraction of patients receiving a full course of neoadjuvant treatment. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Adenocarcinoma/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Resistência a Medicamentos , Humanos , Terapia Neoadjuvante , Organoides/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Neoplasias PancreáticasRESUMO
BACKGROUND: Sensitization to sensory stimuli is an essential feature of migraine attacks. The relationship between the clinical course of migraine and increased sensitivity to olfactory stimuli has been little studied so far. METHODS: We analyzed the frequency and quality of osmophobia depending on the phase of migraine in patients with episodic and chronic migraine treated in an tertiary headache center with regard to gender, age, medical history and migraine disability assessment score (MIDAS). Standardized diagnostic questions were used for the assessment of osmophobia. RESULTS: In our cross-sectional investigation (n = 113), 38.1% of the patients showed an increased preictal hypersensitivity to odors, whereas 61.9% described ictal and 31.9% interictal hypersensitivity to odors, odor-triggered migraine was described in 30.1%. Median migraine disease duration has been statistically significantly longer in patients who suffered from interictal hypersensitivity to odors (28.5 years vs. 20 years; p = 0.012). There was a significant correlation between interictal hypersensitivity and higher age (54.50 vs. 45; p = 0.015). Patients with higher migraine disability in MIDAS experienced more frequently preictal and interictal olfactory sensitization and odor triggered migraine attacks. CONCLUSIONS: In patients with longer migraine disease duration and higher migraine-related impairment, osmophobia was more frequently observed. These results might support the hypothesis of increasing sensitization with increasing burden of migraine.
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Transtornos de Enxaqueca , Transtornos do Olfato , Transtornos Fóbicos , Estudos Transversais , Cefaleia/complicações , Humanos , Transtornos de Enxaqueca/diagnóstico , Transtornos do Olfato/etiologia , Transtornos Fóbicos/diagnósticoRESUMO
BACKGROUND: More than 2/3 of children and adolescents in Germany regularly suffer from headaches. Headache-related limitations in everyday life, school drop-out and educational impairment are common. Structured therapy programs for young headache patients are widely missing. METHODS: One hundred eleven patients with frequent migraine and/or tension type headache were treated in a 15 hour group program in afternoons, parallel with school, parents received 7 hours of therapy. At the beginning of the program (T0), 6 (T1) and 12 months (T2) after completion, data on headache related disability (PedMidas), headache frequency, intensity, and pediatric pain disability score (PPDI) were prospectively collected to investigate the effects of the therapy. RESULTS: Seventy-five patients (9-19 years, median = 14; 66.7% female) and their parents provided patient reported outcome measures showing at T1 (65 patients) and T2 (47 patients) reduced headache frequency (last 3 months headache days median T0: 30 days; T1: 18 days, reduction of median 12 days since T0; T2: 13 days, reduction of median 17 days since T0). Linear mixed models revealed significant reduction (T0/T1 p = 0,002; T0/T2 p = 0,001). Reduced headache disability has been reported at T1 and T2 (PedMidas median T0 = 30, T1 = 15, T2 = 7; p < 0,001, p < 0,001 respectively). Follow up data of a subgroup of patients 24 months after the treatment point to sustainable effects. CONCLUSIONS: The interdisciplinary multimodal headache therapy program DreKiP reduces headache frequency and headache related disability significantly 6-12 months following its completion. TRIAL REGISTRATION: DRKS00027523, retrospectively registered.
Assuntos
Transtornos de Enxaqueca , Cefaleia do Tipo Tensional , Adolescente , Criança , Terapia Combinada , Feminino , Cefaleia/terapia , Humanos , Masculino , Medidas de Resultados Relatados pelo Paciente , Resultado do TratamentoRESUMO
BACKGROUND: Postpancreatectomy haemorrhage (PPH) is a rare but potentially fatal complication after pancreatoduodenectomy. Preventive strategies are lacking with scarce data for support. The aim of this study was to investigate whether a prophylactic falciform ligament wrap around the hepatic and gastroduodenal artery can prevent PPH from these vessels. METHODS: In a randomized, controlled, multicentre trial, patients who were scheduled for elective open partial pancreatoduodenectomy with pancreatojejunostomy between 5 November 2015 and 2 April 2020 were randomly allocated in a 1 : 1 ratio to undergo pancreatoduodenectomy with (intervention) or without (control) a falciform ligament wrap around the hepatic artery. The primary endpoint was the rate of clinically relevant PPH from the hepatic artery or gastroduodenal artery stump within 3 months after pancreatoduodenectomy. Secondary endpoints were the rates of associated postoperative complications, for example postoperative pancreatic fistula (POPF) and PPH. RESULTS: Altogether, 445 patients were randomized with 222 and 223 in each group. Among the patients included in modified intention-to-treat analysis (207 in the intervention group and 210 in the control group), the primary endpoint was observed in six of 207 in the intervention group compared with 15 of 210 in the control group (2.9 versus 7.1 per cent respectively; odds ratio 0.39 (95 per cent c.i. 0.15 to 1.02); P = 0.071). Per protocol analysis showed a significant reduction in the intervention group (odds ratio 0.26 (95 per cent c.i. 0.09 to 0.80); P = 0.017). A soft pancreas texture (43 per cent) and the rate of a clinically relevant POPF were evenly (20 per cent) distributed between the groups. The rate of any clinically relevant PPH including the primary endpoint and other bleeding sites was not significantly different between intervention and control groups (9.7 versus 14.8 per cent respectively). CONCLUSION: A falciform ligament wrap may reduce PPH from the hepatic artery or gastroduodenal artery stump and should be considered during pancreatoduodenectomy. REGISTRATION NUMBER: NCT02588066 (http://www.clinicaltrials.gov).
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Hemostasia Cirúrgica/métodos , Artéria Hepática/cirurgia , Ligamentos/cirurgia , Pancreaticoduodenectomia/métodos , Hemorragia Pós-Operatória/prevenção & controle , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pancreaticoduodenectomia/efeitos adversosRESUMO
The genomic era continues to revolutionize our understanding of the evolution of biodiversity. In phycology, emphasis remains on assembling nuclear and organellar genomes, leaving the full potential of genomic datasets to answer long-standing questions about the evolution of biodiversity largely unexplored. Here, we used whole-genome sequencing (WGS) datasets to survey species diversity in the kelp genus Alaria, compare phylogenetic signals across organellar and nuclear genomes, and specifically test whether phylogenies behave like trees or networks. Genomes were sequenced from across the global distribution of Alaria (including Alaria crassifolia, A. praelonga, A. crispa, A. marginata, and A. esculenta), representing over 550 GB of data and over 2.2 billion paired reads. Genomic datasets retrieved 3,814 and 4,536 single-nucleotide polymorphisms (SNPs) for mitochondrial and chloroplast genomes, respectively, and upwards of 148,542 high-quality nuclear SNPs. WGS revealed an Arctic lineage of Alaria, which we hypothesize represents the synonymized taxon A. grandifolia. The SNP datasets also revealed inconsistent topologies across genomic compartments, and hybridization (i.e., phylogenetic networks) between Pacific A. praelonga, A. crispa, and putative A. grandifolia, and between some lineages of the A. marginata complex. Our analysis demonstrates the potential for WGS data to advance our understanding of evolution and biodiversity beyond amplicon sequencing, and that hybridization is potentially an important mechanism contributing to novel lineages within Alaria. We also emphasize the importance of surveying phylogenetic signals across organellar and nuclear genomes, such that models of mixed ancestry become integrated into our evolutionary and taxonomic understanding.
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Genoma de Cloroplastos , Genoma Mitocondrial , Kelp , Sequência de Bases , Hibridização Genética , Kelp/classificação , Kelp/genética , Filogenia , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA , Sequenciamento Completo do GenomaRESUMO
BACKGROUND & AIMS: Patterns of genetic alterations characterize different molecular subtypes of human gastric cancer. We aimed to establish mouse models of these subtypes. METHODS: We searched databases to identify genes with unique expression in the stomach epithelium, resulting in the identification of Anxa10. We generated mice with tamoxifen-inducible Cre recombinase (CreERT2) in the Anxa10 gene locus. We created 3 mouse models with alterations in pathways that characterize the chromosomal instability (CIN) and the genomically stable (GS) subtypes of human gastric cancer: Anxa10-CreERT2;KrasG12D/+;Tp53R172H/+;Smad4fl/f (CIN mice), Anxa10-CreERT2;Cdh1fl/fl;KrasG12D/+;Smad4fl/fl (GS-TGBF mice), and Anxa10-CreERT2;Cdh1fl/fl;KrasG12D/+;Apcfl/fl (GS-Wnt mice). We analyzed tumors that developed in these mice by histology for cell types and metastatic potential. We derived organoids from the tumors and tested their response to chemotherapeutic agents and the epithelial growth factor receptor signaling pathway inhibitor trametinib. RESULTS: The gastric tumors from the CIN mice had an invasive phenotype and formed liver and lung metastases. The tumor cells had a glandular morphology, similar to human intestinal-type gastric cancer. The gastric tumors from the GS-TGFB mice were poorly differentiated with diffuse morphology and signet ring cells, resembling human diffuse-type gastric cancer. Cells from these tumors were invasive, and mice developed peritoneal carcinomatosis and lung metastases. GS-Wnt mice developed adenomatous tooth-like gastric cancer. Organoids derived from tumors of GS-TGBF and GS-Wnt mice were more resistant to docetaxel, whereas organoids from the CIN tumors were more resistant to trametinib. CONCLUSIONS: Using a stomach-specific CreERT2 system, we created mice that develop tumors with morphologic similarities to subtypes of human gastric cancer. These tumors have different patterns of local growth, metastasis, and response to therapeutic agents. They can be used to study different subtypes of human gastric cancer.
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Modelos Animais de Doenças , Mucosa Gástrica/patologia , Loci Gênicos/genética , Neoplasias Gástricas/genética , Proteína da Polipose Adenomatosa do Colo/genética , Animais , Anexinas/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Transformação Celular Neoplásica/genética , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Integrases/genética , Masculino , Camundongos , Camundongos Transgênicos , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína Smad4/genética , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Proteína Supressora de Tumor p53/genéticaRESUMO
In kinship analysis, large data sets with estimated haplotype frequencies for marker clusters are very important for the likelihood calculation. Practical use of the X-STRs demonstrated that in some complex kinship cases, the marker set of the Investigator Argus X-12 kit can be insufficient. This study aimed to extend the German data base of the Argus X-12 kit (1037 haplotypes) and for a cluster in Xq21 (806 haplotypes) with additional 700 male haplotypes and to include a further cluster in Xp22.3 to complete the X-STR marker set for complex kinship cases.
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Cromossomos Humanos X , Ligação Genética , Haplótipos , Desequilíbrio de Ligação , Repetições de Microssatélites , Reação em Cadeia da Polimerase/métodos , Bases de Dados Genéticas , Genética Populacional , Alemanha , Humanos , MasculinoRESUMO
Currently, voided urine cytology (VUC) serves as the gold standard for the detection of bladder cancer (BCa) in urine. Despite its high specificity, VUC has shortcomings in terms of sensitivity. Therefore, alternative biomarkers are being searched, which might overcome these disadvantages as a useful adjunct to VUC. The aim of this study was to evaluate the diagnostic potential of the urinary levels of selected microRNAs (miRs), which might represent such alternative biomarkers due to their BCa-specific expression. Expression levels of nine BCa-associated microRNAs (miR-21, -96, -125b, -126, -145, -183, -205, -210, -221) were assessed by quantitative PCR in urine sediments from 104 patients with primary BCa and 46 control subjects. Receiver operating characteristic (ROC) curve analyses revealed a diagnostic potential for miR-96, -125b, -126, -145, -183, and -221 with area under the curve (AUC) values between 0.605 and 0.772. The combination of the four best candidates resulted in sensitivity, specificity, positive and negative predictive values (NPV), and accuracy of 73.1%, 95.7%, 97.4%, 61.1%, and 80.0%, respectively. Combined with VUC, sensitivity and NPV could be increased by nearly 8%, each surpassing the performance of VUC alone. The present findings suggested a diagnostic potential of miR-125b, -145, -183, and -221 in combination with VUC for non-invasive detection of BCa in urine.
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Biomarcadores Tumorais/urina , Carcinoma/urina , MicroRNAs/urina , Neoplasias da Bexiga Urinária/urina , Idoso , Biomarcadores Tumorais/normas , Carcinoma/diagnóstico , Feminino , Humanos , Masculino , MicroRNAs/normas , Sensibilidade e Especificidade , Neoplasias da Bexiga Urinária/diagnósticoRESUMO
BACKGROUND/OBJECTIVE: Headache in pupils is underestimated and has a negative impact on learning and life. The aim of this study was to investigate headache prevalence and its collateral effects, in pupils of different ages and school types in a German city. METHODS: Anonymized questionnaires were distributed to 5419 pupils attending primary and secondary schools. Demographics, headache frequency, analgesic use, school absence and, for secondary school children, data on lifestyle were collected. RESULTS: The questionnaire was returned by 2706 children (49%), 1362 (50.3%) girls, 1344 (49.7%) boys. Of these, 36.6% indicated a frequency of 1, and 31.5% a frequency of ≥ 2 headache days per month within the last 3 months. Headache prevalence increased with school grade, age and secondary school type: 63.6%, 67.2% and 79.5% for primary school children, pupils attending 8-year and pupils attending 6-year secondary schools, respectively. With secondary school level I certificates, pupils are prepared for general professional training in 6 years. Secondary school level II results, after 8 years of training, in university entrance level II certificates, which are the precondition for university studies. Girls reported significantly more headache than boys (73% vs. 63.1%). A significant relationship has been observed between headache frequency and school absence and between headache intensity and headache frequency. Of pupils with headache at least twice a month, 48.1% reported analgesic intake. Ibuprofen (49.1%) and paracetamol (32.8%) were the most frequently used analgesics. Of those pupils with headache ≥ 2 days/month, 68.3% did not have a specific headache diagnosis. Concomitant diseases and regular drug intake, analgesic intake for another reason than headache, caffeine consumption and lack of participation in sports were positively correlated with headache. CONCLUSIONS: The majority of pupils suffer from headache at least once a month. Since frequent headache results in educational and social limitations, pupils at risk should be identified and referred to headache education programs. Efforts are needed to improve the management of juvenile headache patients.
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Cefaleia/diagnóstico , Cefaleia/epidemiologia , Habitação/tendências , Instituições Acadêmicas/tendências , Estudantes , Adolescente , Criança , Estudos Transversais , Feminino , Alemanha/epidemiologia , Cefaleia/economia , Habitação/economia , Humanos , Masculino , Prevalência , Instituições Acadêmicas/economia , Inquéritos e QuestionáriosRESUMO
The prenatal finding of a small supernumerary marker chromosome (sSMC) is a challenge for genetic counseling. Our analytic algorithm is based on sSMC frequencies and multicolor FISH to accelerate the procedure. The chromosomal origin, size, and degree of mosaicism of the sSMC then determine the prognosis. We illustrate the effectiveness on 4 prenatally identified de novo mosaic sSMCs derived from chromosomes 13/21, X, 3, and 17. Three sSMC carriers had a good prognosis and apparently healthy children were born, showing no abnormality till the last examination at the age of 4 years. One case had a poor prognosis, and the parents decided to terminate the pregnancy. Our work contributes to the laboratory and clinical management of prenatally detected sSMCs. FISH is a reliable method for fast sSMC evaluation and prognosis assessment; it prevents unnecessary delays and uncertainty, allows informed decision making, and reduces unnecessary pregnancy terminations.
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Aberrações Cromossômicas , Heterozigoto , Diagnóstico Pré-Natal , Adulto , Algoritmos , Pré-Escolar , Feminino , Estudos de Associação Genética , Aconselhamento Genético , Humanos , Hibridização in Situ Fluorescente , Lactente , Cariotipagem , Masculino , Idade Materna , Gravidez , PrognósticoRESUMO
INTRODUCTION: The morphology of the vocal tract plays a crucial role in singing. Adjustments of the lower part of the vocal tract are essential for voice quality and timbre. Structured investigations of this region are challenging due to the small extent of the morphological modifications. MATERIAL AND METHODS: This study analyzed the morphology of the endolaryngeal tube and parts of the surrounding hypopharynx for the sustained vowels /a/, /e/, /i/, //, and // by 11 female singer subjects who were at the beginning of their academic singing studies. As in a previous study with male subjects, analysis was based on two phonatory conditions: a natural, speech-like phonation and a singing phonation, like in classical singing. By means of 3D image processing from magnetic resonance imaging, multiple measures were derived. The data were statistically analyzed using linear mixed effects models and ANOVA. RESULTS: The female singers enlarged the ratio of the endolaryngeal tube to the adjacent hypopharynx for singing. DISCUSSION: In contrast to the findings of the male singers in a previous study, the ratios of the laryngeal volumes to the neighboring hypopharynx increased while singing. The female singer subjects of the present study increased those ratios, mediated by an over-proportional enlargement of the endolaryngeal tube. Existing acoustic differences to male singers are thus given a morphological basis. CONCLUSION: The study gives insight into the characteristic adjustments of the vocal tract of female classical singers. The resonatory strategies for females in classical singing differ from those found in males.
RESUMO
BACKGROUND: We studied UPBEAT1 (UPB1) which regulated superoxide radical / hydrogen peroxide ratio together with peroxidase (POD) activity and PAL genes expression under different ways of apical meristem development during the xylem structural elements' formation in unique woody plants B. pendula var. pendula with straight-grained wood and B. pendula var. carelica with figured wood. The differentiation process predominanced in straight-grained wood (B. pendula var. pendula) or proliferation - in the figured wood. The investigation was conducted in the radial row (cambial zone - differentiating xylem - mature xylem) during the active cambial growth period. OBJECTIVE: The study aimed to study the xylogenesis processes occurring in the 16-year-old straight-grained silver birch (Betula pendula Roth) and Karelian birch (Betula pendula Roth var. carelica (Mercl.) Hämet-Ahti) with figured wood. METHODS: Hydrogen peroxide and superoxide radical contents and peroxidase activity were determined spectrophotometrically. Gene expression for PAL family genes and the UPBEAT1 gene was assessed using qRT-PCR. RESULTS: Principal component analysis has confirmed trees with straight-grained and figured wood to be different according to UPBEAT1-ROS-POD-PAL system functioning. CONCLUSION: The higher superoxide radical/hydrogen peroxide ratio in figured Karelian birch, along with UPBEAT1 transcription factor and PAL genes upregulation, distinguished it from straight-grained silver birch. This metabolic picture confirmed the shift of Karelian birch xylogenesis towards proliferation processes, accompanied by ROS and phenolic compounds' flow and POD activity.
Assuntos
Betula , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas , Xilema , Betula/genética , Betula/crescimento & desenvolvimento , Betula/metabolismo , Xilema/metabolismo , Xilema/genética , Xilema/crescimento & desenvolvimento , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Peróxido de Hidrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Peroxidase/metabolismo , Peroxidase/genética , Superóxidos/metabolismo , Madeira/metabolismo , Madeira/crescimento & desenvolvimento , Madeira/genéticaRESUMO
Background: Age reportedly affects headache prevalence differently in boys and girls. However, little empirical data exists regarding pediatric headache prevalence and headache-related burden in children and adolescents according to age and sex. In the present study, we considered age and sex while evaluating the distribution, characteristics, and impairment of primary headache disorders at a pediatric headache center in Germany. Methods: Medical records of children and adolescents attending the headache clinic of the Interdisciplinary Pain Center of the Carl Gustav Carus University Hospital in Dresden during the period 2015-2022 were retrospectively grouped and analyzed depending on age (< or ≥14 years) and sex. Results: The study population consisted of 652 children and adolescents, aged between 3 and 18 years. Almost two-thirds of the patients (≈60%) were females, and almost two-thirds of these females (58%) were ≥14 years of age. Generally, the most prevalent headache diagnoses as defined by the International Classification of Headache Disorders 3rd edition were episodic migraine without aura and the combination of tension-type headache and episodic migraine with or without aura i.e., mixed-type headache (each ≈27%). In the younger group (<14 years), the mixed-type headache was the most prevalent in girls (28.6%), whereas, for boys, episodic migraine without aura was the most prevalent headache diagnosis (47.4%). In the older group (≥14 years), the mixed-type headache continued to be the most prevalent for girls (30%), and it became the most prevalent for boys (26.3%). Before the age of 14, about 16% of children were severely affected by their headaches. After the age of 14, this proportion increased to roughly one-third (33%) of adolescents, driven mainly by teenage girls (26%) who were severely affected by their headaches. Furthermore, the prevalence of comorbidities was significantly higher among girls (67%), particularly in the adolescent group (74%). Conclusions: Our data shows that headache disorders in a specialized pediatric clinic impose a significant burden, especially among teenage girls indicating high therapy needs. Enhancing awareness of early diagnosis and preventive care is crucial to mitigate the development of chronic headaches, and mitigate their adverse effects on life quality and educational capability.