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1.
Cell ; 183(6): 1617-1633.e22, 2020 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-33259802

RESUMO

Histone H3.3 glycine 34 to arginine/valine (G34R/V) mutations drive deadly gliomas and show exquisite regional and temporal specificity, suggesting a developmental context permissive to their effects. Here we show that 50% of G34R/V tumors (n = 95) bear activating PDGFRA mutations that display strong selection pressure at recurrence. Although considered gliomas, G34R/V tumors actually arise in GSX2/DLX-expressing interneuron progenitors, where G34R/V mutations impair neuronal differentiation. The lineage of origin may facilitate PDGFRA co-option through a chromatin loop connecting PDGFRA to GSX2 regulatory elements, promoting PDGFRA overexpression and mutation. At the single-cell level, G34R/V tumors harbor dual neuronal/astroglial identity and lack oligodendroglial programs, actively repressed by GSX2/DLX-mediated cell fate specification. G34R/V may become dispensable for tumor maintenance, whereas mutant-PDGFRA is potently oncogenic. Collectively, our results open novel research avenues in deadly tumors. G34R/V gliomas are neuronal malignancies where interneuron progenitors are stalled in differentiation by G34R/V mutations and malignant gliogenesis is promoted by co-option of a potentially targetable pathway, PDGFRA signaling.


Assuntos
Neoplasias Encefálicas/genética , Carcinogênese/genética , Glioma/genética , Histonas/genética , Interneurônios/metabolismo , Mutação/genética , Células-Tronco Neurais/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Neoplasias Encefálicas/patologia , Carcinogênese/patologia , Linhagem da Célula , Reprogramação Celular/genética , Cromatina/metabolismo , Embrião de Mamíferos/metabolismo , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Glioma/patologia , Histonas/metabolismo , Lisina/metabolismo , Camundongos Endogâmicos C57BL , Modelos Biológicos , Gradação de Tumores , Oligodendroglia/metabolismo , Regiões Promotoras Genéticas/genética , Prosencéfalo/embriologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Transcrição Gênica , Transcriptoma/genética
2.
Nature ; 576(7786): 274-280, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31802000

RESUMO

Embryonal tumours with multilayered rosettes (ETMRs) are aggressive paediatric embryonal brain tumours with a universally poor prognosis1. Here we collected 193 primary ETMRs and 23 matched relapse samples to investigate the genomic landscape of this distinct tumour type. We found that patients with tumours in which the proposed driver C19MC2-4 was not amplified frequently had germline mutations in DICER1 or other microRNA-related aberrations such as somatic amplification of miR-17-92 (also known as MIR17HG). Whole-genome sequencing revealed that tumours had an overall low recurrence of single-nucleotide variants (SNVs), but showed prevalent genomic instability caused by widespread occurrence of R-loop structures. We show that R-loop-associated chromosomal instability can be induced by the loss of DICER1 function. Comparison of primary tumours and matched relapse samples showed a strong conservation of structural variants, but low conservation of SNVs. Moreover, many newly acquired SNVs are associated with a mutational signature related to cisplatin treatment. Finally, we show that targeting R-loops with topoisomerase and PARP inhibitors might be an effective treatment strategy for this deadly disease.


Assuntos
MicroRNAs/genética , Neoplasias Embrionárias de Células Germinativas/genética , RNA Helicases DEAD-box/genética , DNA Topoisomerases Tipo I/genética , Humanos , Mutação , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Inibidores de Poli(ADP-Ribose) Polimerases , Poli(ADP-Ribose) Polimerases/genética , Polimorfismo de Nucleotídeo Único , RNA Longo não Codificante , Recidiva , Ribonuclease III/genética
3.
Analyst ; 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38864551

RESUMO

A proof-of-concept study of the utilization of a single mass spectrometer for qualitative molecular analysis as well as for quantitative metal determination is described. This was performed with an argon microwave plasma as the ion source coupled to an ion trap mass spectrometer. A microwave induced plasma with tuneable power and gas flow rate was loaded with dried nebulized sample solutions. The commercially available plasma torch was slightly modified to allow the introduction of the sample in different regions of the plasma. Using soft settings, organic compounds introduced in the plasma plume could be detected as protonated molecular ions. Under harsher conditions, elemental analysis was demonstrated for several metals. Lead could be determined with a limit of detection of 150 nM. Minor on-the-fly adjustments of the power, flow rate and sampling distance allowed a mild fragmentation of organic compounds. Ionization differences observed were rationalized by emission spectroscopy, and excitation and rotational temperatures were determined. Simultaneous determination of elemental and molecular information was demonstrated for a rubidium-crown-ether complex. The maximum argon gas consumption for these tasks was below 2 L min-1 and the maximal power used was 90 W.

4.
Br J Cancer ; 129(3): 455-465, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37340093

RESUMO

BACKGROUND: Recurrent genetic lesions provide basis for risk assessment in pediatric acute lymphoblastic leukemia (ALL). However, current prognostic classifiers rely on a limited number of predefined sets of alterations. METHODS: Disease-relevant copy number aberrations (CNAs) were screened genome-wide in 260 children with B-cell precursor ALL. Results were integrated with cytogenetic data to improve risk assessment. RESULTS: CNAs were detected in 93.8% (n = 244) of the patients. First, cytogenetic profiles were combined with IKZF1 status (IKZF1normal, IKZF1del and IKZF1plus) and three prognostic subgroups were distinguished with significantly different 5-year event-free survival (EFS) rates, IKAROS-low (n = 215): 86.3%, IKAROS-medium (n = 27): 57.4% and IKAROS-high (n = 18): 37.5%. Second, contribution of genetic aberrations to the clinical outcome was assessed and an aberration-specific score was assigned to each prognostically relevant alteration. By aggregating the scores of aberrations emerging in individual patients, personalized cumulative values were calculated and used for defining four prognostic subgroups with distinct clinical outcomes. Two favorable subgroups included 60% of patients (n = 157) with a 5-year EFS of 96.3% (excellent risk, n = 105) and 87.2% (good risk, n = 52), respectively; while 40% of patients (n = 103) showed high (n = 74) or ultra-poor (n = 29) risk profile (5-year EFS: 67.4% and 39.0%, respectively). CONCLUSIONS: PersonALL, our conceptually novel prognostic classifier considers all combinations of co-segregating genetic alterations, providing a highly personalized patient stratification.


Assuntos
Linfoma de Burkitt , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Medição de Risco , Fator de Transcrição Ikaros/genética , Deleção de Genes
5.
Anal Chem ; 95(28): 10777-10784, 2023 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-37407429

RESUMO

An easily built drift tube instrument with ring electrodes made of rolled-up flexible printed circuit boards is reported. Its resolving power was maximized by careful attention to the drift tube geometry and the response time of the detector amplifier and by employing a high separation field strength. The separation of singly charged aliphatic quaternary ammonium ions introduced by electrospray was performed, and the measured resolving power was between 86 and 97% of the theoretical limit for three different drift tube lengths investigated. For the longest drift length of 30 cm, a resolving power of up to 228 was obtained. Three benzalkonium chlorides were also separated with resolving powers of over 210. The tristate injection scheme can also be used, with only a small loss of the separation performance compared to the two-state injection.

6.
Acta Neuropathol ; 146(3): 527-541, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37450044

RESUMO

Atypical teratoid/rhabdoid tumors (AT/RT) are the most common malignant brain tumors manifesting in infancy. They split into four molecular types. The major three (AT/RT-SHH, AT/RT-TYR, and AT/RT-MYC) all carry mutations in SMARCB1, the fourth quantitatively smaller type is characterized by SMARCA4 mutations (AT/RT-SMARCA4). Molecular characteristics of disease recurrence or metastatic spread, which go along with a particularly dismal outcome, are currently unclear. Here, we investigated tumor tissue from 26 patients affected by AT/RT to identify signatures of recurrences in comparison with matched primary tumor samples. Microscopically, AT/RT recurrences demonstrated a loss of architecture and significantly enhanced mitotic activity as compared to their related primary tumors. Based on DNA methylation profiling, primary tumor and related recurrence were grossly similar, but three out of 26 tumors belonged to a different molecular type or subtype after second surgery compared to related primary lesions. Copy number variations (CNVs) differed in six cases, showing novel gains on chromosome 1q or losses of chromosome 10 in recurrences as the most frequent alterations. To consolidate these observations, our cohort was combined with a data set of unmatched primary and recurrent AT/RT, which demonstrated chromosome 1q gain and 10 loss in 18% (n = 7) and 11% (n = 4) of the recurrences (n = 38) as compared to 7% (n = 3) and 0% (n = 0) in the primary tumors (n = 44), respectively. Similar to the observations made by DNA methylation profiling, RNA sequencing of our cohort revealed AT/RT primary tumors and matched recurrences clustering closely together. However, a number of genes showed significantly altered expression in AT/RT-SHH recurrences. Many of them are known tumor driving growth factors, involved in embryonal development and tumorigenesis, or are cell-cycle-associated. Overall, our work identifies subtle molecular changes that occur in the course of the disease and that may help define novel therapeutic targets for AT/RT recurrences.


Assuntos
Variações do Número de Cópias de DNA , Progressão da Doença , Epigênese Genética , Perfilação da Expressão Gênica , Recidiva , Tumor Rabdoide , Teratoma , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 10/genética , Estudos de Coortes , Células Dendríticas , Variações do Número de Cópias de DNA/genética , Metilação de DNA , Histologia , Mitose , Tumor Rabdoide/classificação , Tumor Rabdoide/genética , Tumor Rabdoide/imunologia , Tumor Rabdoide/patologia , Análise de Sequência de RNA , Teratoma/classificação , Teratoma/genética , Teratoma/imunologia , Teratoma/patologia , Fatores de Transcrição/genética , Regulação Neoplásica da Expressão Gênica/genética
7.
Acta Neuropathol ; 143(6): 697-711, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35501487

RESUMO

Atypical teratoid/rhabdoid tumor (ATRT) is an aggressive central nervous system tumor characterized by loss of SMARCB1/INI1 protein expression and comprises three distinct molecular groups, ATRT-TYR, ATRT-MYC and ATRT-SHH. ATRT-SHH represents the largest molecular group and is heterogeneous with regard to age, tumor location and epigenetic profile. We, therefore, aimed to investigate if heterogeneity within ATRT-SHH might also have biological and clinical importance. Consensus clustering of DNA methylation profiles and confirmatory t-SNE analysis of 65 ATRT-SHH yielded three robust molecular subgroups, i.e., SHH-1A, SHH-1B and SHH-2. These subgroups differed by median age of onset (SHH-1A: 18 months, SHH-1B: 107 months, SHH-2: 13 months) and tumor location (SHH-1A: 88% supratentorial; SHH-1B: 85% supratentorial; SHH-2: 93% infratentorial, often extending to the pineal region). Subgroups showed comparable SMARCB1 mutational profiles, but pathogenic/likely pathogenic SMARCB1 germline variants were over-represented in SHH-2 (63%) as compared to SHH-1A (20%) and SHH-1B (0%). Protein expression of proneural marker ASCL1 (enriched in SHH-1B) and glial markers OLIG2 and GFAP (absent in SHH-2) as well as global mRNA expression patterns differed, but all subgroups were characterized by overexpression of SHH as well as Notch pathway members. In a Drosophila model, knockdown of Snr1 (the fly homologue of SMARCB1) in hedgehog activated cells not only altered hedgehog signaling, but also caused aberrant Notch signaling and formation of tumor-like structures. Finally, on survival analysis, molecular subgroup and age of onset (but not ASCL1 staining status) were independently associated with overall survival, older patients (> 3 years) harboring SHH-1B experiencing relatively favorable outcome. In conclusion, ATRT-SHH comprises three subgroups characterized by SHH and Notch pathway activation, but divergent molecular and clinical features. Our data suggest that molecular subgrouping of ATRT-SHH has prognostic relevance and might aid to stratify patients within future clinical trials.


Assuntos
Neoplasias do Sistema Nervoso Central , Neoplasias Neuroepiteliomatosas , Tumor Rabdoide , Teratoma , Neoplasias do Sistema Nervoso Central/genética , Metilação de DNA , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , Neoplasias Neuroepiteliomatosas/genética , Prognóstico , Tumor Rabdoide/genética , Proteína SMARCB1/genética , Proteína SMARCB1/metabolismo , Teratoma/genética
8.
Nutr Cancer ; 74(1): 184-192, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-33432830

RESUMO

Cancer is one of the leading causes of death for children; however, appropriate nutritional status can positively affect survival. The aim of this study was to determine to what extent malnutrition risk screening and intensified nutrition support, provided by a professional team, promoted disease progression and survival in pediatric patients with solid tumors. 145 pediatric cancer patients (average age 6.3 ± 5.6 and 6.7 ± 5.4 years) with solid tumors undergoing chemotherapy participated in the study. Two 3-year periods were studied: 2009-2011 and 2012-2014. Patient characteristics and treatment protocols were identical, but in Period 2, with the foundation of our nutrition support team malnutrition risk screening was made mandatory upon every hospital admission. As a result of intensified nutrition support the time from diagnosis to completion of treatment (802 vs. 512 day, p < 0.001) and the need for antimycotic treatment reduced significantly (47.8% vs. 29.1%, p = 0.036). The total percentage of surviving children was 60.3% and 75.0% in Period 1 and 2 respectively. Decrease in weight-for-height percentile during treatment and central nervous system tumors are significant predictors of a less favorable survival. Malnutrition risk screening and intensified nutrition therapy have positive effects on nutritional status and therefore patient survival in pediatric cancer patients.


Assuntos
Desnutrição , Neoplasias , Criança , Pré-Escolar , Progressão da Doença , Humanos , Lactente , Desnutrição/diagnóstico , Neoplasias/complicações , Neoplasias/terapia , Avaliação Nutricional , Estado Nutricional , Apoio Nutricional
9.
Anal Bioanal Chem ; 414(14): 4059-4066, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35381854

RESUMO

The analysis of tobramycin was demonstrated successfully as an example for electrospray ionization on an open-source hardware ion mobility spectrometer. This instrument was assembled inexpensively in-house, and required only very few purpose-made components. The quantitative determination of tobramycin required 20 s for a reading. The calibration curve for the range from 50 to 200 µM was found to be linear with a correlation coefficient of r = 0.9994. A good reproducibility was obtained (3% relative standard deviation) and the limit of detection was determined as 8 µM. As the concentration of the active ingredient in the eye drops (ophthalmic solutions) is too high for the sensitivity of the instrument, the samples had to be diluted appropriately.


Assuntos
Espectrometria de Massas por Ionização por Electrospray , Tobramicina , Calibragem , Soluções Oftálmicas , Reprodutibilidade dos Testes
10.
Childs Nerv Syst ; 38(8): 1479-1485, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35759029

RESUMO

PURPOSE: Cerebellar mutism syndrome (CMS) is a severe neurological complication of posterior fossa tumour surgery in children, and postoperative speech impairment (POSI) is the main component. Left-handedness was previously suggested as a strong risk factor for POSI. The aim of this study was to investigate the relationship between handedness and the risk of POSI. METHODS: We prospectively included children (aged < 18 years) undergoing surgery for posterior fossa tumours in 26 European centres. Handedness was assessed pre-operatively and postoperative speech status was categorised as either POSI (mutism or reduced speech) or habitual speech, based on the postoperative clinical assessment. Logistic regression was used in the risk factor analysis of POSI as a dichotomous outcome. RESULTS: Of the 500 children included, 37 (7%) were excluded from the present analysis due to enrolment at a reoperation; another 213 (43%) due to missing data about surgery (n = 37) and/or handedness (n = 146) and/or postoperative speech status (n = 53). Out of the remaining 250 (50%) patients, 20 (8%) were left-handed and 230 (92%) were right-handed. POSI was observed equally frequently regardless of handedness (5/20 [25%] in left-handed, 61/230 [27%] in right-handed, OR: 1.08 [95% CI: 0.40-3.44], p = 0.882), also when adjusted for tumour histology, location and age. CONCLUSION: We found no difference in the risk of POSI associated with handedness. Our data do not support the hypothesis that handedness should be of clinical relevance in the risk assessment of CMS.


Assuntos
Doenças Cerebelares , Neoplasias Cerebelares , Neoplasias Infratentoriais , Mutismo , Doenças Cerebelares/complicações , Neoplasias Cerebelares/cirurgia , Criança , Lateralidade Funcional , Humanos , Neoplasias Infratentoriais/complicações , Neoplasias Infratentoriais/cirurgia , Mutismo/complicações , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Estudos Prospectivos , Fatores de Risco , Fala
11.
Sensors (Basel) ; 22(4)2022 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-35214593

RESUMO

The composition of gas mixtures may be determined via changes of the speed of sound. As this affects the resonance frequency of the gas inside a tube, indirect measurements through a frequency analysis are also possible. It is demonstrated that this may be carried out with unprecedented simplicity by the novel employment of a piezoelectric tube which serves at the same time as a resonance tube and as transducer into the electronic domain. Experiments were run using a simple diecast aluminum box as the measuring cell, inside which the piezoelectric tube made from lead zirconium titanate with 30-mm length and 5.35-mm inner diameter was suspended. A small loudspeaker placed into the cell served for excitation of the resonance. Peak frequencies between 3910 and 14,590 Hz (for pure CO2 and He, respectively) were obtained. Two component mixtures of O2/N2, CO2/N2, and He/N2 at various composition were tested. A linear frequency change from 4790 to 5100 Hz was observed when going from pure O2 to pure N2.


Assuntos
Gases , Vibração
12.
Electrophoresis ; 42(11): 1209-1216, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33651405

RESUMO

Oxidative damage of biopharmaceuticals during manufacturing and storage is a key concern throughout pharmaceutical development. However, few simple and robust analytical methods are available for the determination of oxidation sites. Here, the potential of affinity capillary electrophoresis (ACE) in the separation of proteins with oxidized methionine (Met) residues is shown. Silver(I) and gold(I) ions have the attribute to selectively form complexes with thioethers over sulfoxides. The addition of these ions to the BGE leads to a selective complexation of Met residues and, thus, to a change of charge allowing separation of species according to the different oxidation states of Met. The mechanisms of these interactions are discussed and binding constants for peptides containing Met with silver(I) are calculated. Additionally, the proposed method can be used as an indicator of oxidative stress in large proteins. The presented technique is easily accessible, economical, and has rapid analysis times, adding new approaches to the analytical toolbox of Met sulfoxide detection.


Assuntos
Ouro , Metionina , Proteínas , Prata , Cátions , Eletroforese Capilar , Metionina/química , Oxirredução , Proteínas/química
13.
Acta Neuropathol ; 142(5): 859-871, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34409497

RESUMO

Medulloblastoma, a common pediatric malignant central nervous system tumour, represent a small proportion of brain tumours in adults. Previously it has been shown that in adults, Sonic Hedgehog (SHH)-activated tumours predominate, with Wingless-type (WNT) and Group 4 being less common, but molecular risk stratification remains a challenge. We performed an integrated analysis consisting of genome-wide methylation profiling, copy number profiling, somatic nucleotide variants and correlation of clinical variables across a cohort of 191 adult medulloblastoma cases identified through the Medulloblastoma Advanced Genomics International Consortium. We identified 30 WNT, 112 SHH, 6 Group 3, and 41 Group 4 tumours. Patients with SHH tumours were significantly older at diagnosis compared to other subgroups (p < 0.0001). Five-year progression-free survival (PFS) for WNT, SHH, Group 3, and Group 4 tumours was 64.4 (48.0-86.5), 61.9% (51.6-74.2), 80.0% (95% CI 51.6-100.0), and 44.9% (95% CI 28.6-70.7), respectively (p = 0.06). None of the clinical variables (age, sex, metastatic status, extent of resection, chemotherapy, radiotherapy) were associated with subgroup-specific PFS. Survival among patients with SHH tumours was significantly worse for cases with chromosome 3p loss (HR 2.9, 95% CI 1.1-7.6; p = 0.02), chromosome 10q loss (HR 4.6, 95% CI 2.3-9.4; p < 0.0001), chromosome 17p loss (HR 2.3, 95% CI 1.1-4.8; p = 0.02), and PTCH1 mutations (HR 2.6, 95% CI 1.1-6.2; p = 0.04). The prognostic significance of 3p loss and 10q loss persisted in multivariable regression models. For Group 4 tumours, chromosome 8 loss was strongly associated with improved survival, which was validated in a non-overlapping cohort (combined cohort HR 0.2, 95% CI 0.1-0.7; p = 0.007). Unlike in pediatric medulloblastoma, whole chromosome 11 loss in Group 4 and chromosome 14q loss in SHH was not associated with improved survival, where MYCN, GLI2 and MYC amplification were rare. In sum, we report unique subgroup-specific cytogenetic features of adult medulloblastoma, which are distinct from those in younger patients, and correlate with survival disparities. Our findings suggest that clinical trials that incorporate new strategies tailored to high-risk adult medulloblastoma patients are urgently needed.


Assuntos
Neoplasias Cerebelares/genética , Meduloblastoma/genética , Adolescente , Adulto , Biomarcadores Tumorais/genética , Neoplasias Cerebelares/mortalidade , Neoplasias Cerebelares/patologia , Estudos de Coortes , Feminino , Humanos , Masculino , Meduloblastoma/mortalidade , Meduloblastoma/patologia , Intervalo Livre de Progressão , Fatores de Risco , Adulto Jovem
14.
Pediatr Blood Cancer ; 68(12): e29267, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34347371

RESUMO

BACKGROUND: Refined therapy has helped to improve survival rates in rhabdoid tumors (RT). Prognosis for patients with chemoresistant, recurrent, or progressive RT remains dismal. Although decitabine, an epigenetically active agent, has mainly been evaluated in the management of hematologic malignancies in adults, safety in children has also been demonstrated repeatedly. MATERIALS AND METHODS: A retrospective series of patients who received decitabine upon relapse or progression following therapy according to the EU-RHAB regimen is presented. Due to the retrospective nature of analyses, response was defined as measurable regression of at least one lesion on imaging. 850k methylation profiling was done whenever tumor tissue was available. RESULTS: A total of 22 patients with RT of any anatomical localization were included. Most patients (19/22) presented with metastases. All received low-dose decitabine with or preceding conventional chemotherapy. Patients received a median of two (1-6) courses of decitabine; 27.3% (6/22) demonstrated a radiological response. Molecular analyses revealed increased methylation levels in tumors from responders. No excessive toxicity was observed. Clinical benefits for responders included eligibility for early phase trials or local therapy. Responders showed prolonged time to progression and overall survival. Due to small sample size, statistical correction for survivorship bias demonstrated no significant effect on survival for responders. CONCLUSIONS: Patients with RT demonstrate promising signs of antitumor activity after multiagent relapse therapy including decitabine. Analyses of methylation data suggest a specific effect on an epigenetic level. We propose to consider decitabine and other epigenetic drugs as candidates for further clinical investigations in RT.


Assuntos
Tumor Rabdoide , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Azacitidina/uso terapêutico , Criança , Decitabina/uso terapêutico , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Prognóstico , Estudos Retrospectivos , Tumor Rabdoide/tratamento farmacológico , Tumor Rabdoide/genética
15.
Am J Addict ; 30(6): 570-577, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34414623

RESUMO

BACKGROUND AND OBJECTIVES: Alcohol use disorder (AUD) is common and causes significant morbidity and mortality. Currently approved medications are moderately effective. Novel medications are needed to address AUD. Preliminary data suggests pioglitazone may reduce alcohol use. METHODS: Veterans seen at the Minneapolis VA Health Care System, who were prescribed pioglitazone for diabetes between October 1, 2015 and September 30, 2016, were identified using a national VA database (N = 49). Further chart review was performed to identify all Alcohol Use Disorder Identification Test-Consumption (AUDIT-C) scores prior to starting pioglitazone. Hierarchical Linear models were used to compare all AUDIT-C scores on and off pioglitazone and compare the change in AUDIT-C scores over time before and during pioglitazone was prescribed. AUDIT-C scores were nested within subject with fixed effects for pioglitazone and random intercept and slope for time. RESULTS: Forty-nine patients were prescribed pioglitazone and had AUDIT-C scores of 3 or more. The estimated mean AUDIT-C score prior to receiving pioglitazone was 3.98 (95% confidence interval [CI]: 3.51-4.44) and this was reduced to 2.89 (95% CI: 2.46-3.32), reflecting a significant change F(1, 323) = 43.3, p < .001 in the score. The primary reduction occurred within the first year of the pioglitazone prescription. This effect remained significant after controlling for age. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: This is the first study of pioglitazone used in a clinical sample focused on alcohol use outcome. The data show that pioglitazone may reduce alcohol use in patients with heavy drinking. Clinical trials of pioglitazone are warranted in patients with AUD.


Assuntos
Alcoolismo , Veteranos , Consumo de Bebidas Alcoólicas , Alcoolismo/tratamento farmacológico , Alcoolismo/epidemiologia , Humanos , Pioglitazona/uso terapêutico
16.
Electrophoresis ; 2020 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-32895993

RESUMO

A CE instrument that can be assembled from commercially available components with minimal construction effort is described. Except for the electronic control circuitry no specially made parts are required. It is based on a flexible design of microfluidic, electropneumatic, and electronic sections and different configurations can easily be implemented. Automated injection into the capillary is performed hydrodynamically by the application of a pressure for a controlled length of time. The performance of the device was tested with a contactless conductivity detector by separating different metal ions. In addition, nine metal cations related to the quality of honey were separated in 2.3 min and four honey samples were analysed quantitatively to demonstrate the applicability of the method.

17.
Electrophoresis ; 41(23): 1980-1990, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32856726

RESUMO

In this study, the development of our purpose-made capacitively coupled contactless conductivity detection (C4 D) for CE is reported. These systems have been employed as a simple, versatile, and cost-effective analytical tool. CE-C4 D devices, whose principle is based on the control of the ion movements under an electrical field, can be constructed even with a modest financial budget and limited infrastructure. A featured application was developed for quality control of antimicrobial drugs using CE-C4 D, with most recent work on determination of aminoglycoside and glycopeptide antibiotics being communicated. For aminoglycosides, the development of CE-C4 D methods was adapted to two categories. The first one includes drugs (liquid or powder form) for intravenous injection, containing either amikacin, streptomycin, kanamycin A, or kanamycin B. The second one covers drugs for eye drops (liquid or ointment form), containing either neomycin, tobramycin, or polymyxin. The CE-C4 D method development was also made for determination of some popular glycopeptide antibiotics in Vietnam, including vancomycin and teicoplanin. The best detection limit achieved using the developed CE-C4 D methods was 0.5 mg/L. Good agreement between results from CE-C4 D and the confirmation method (HPLC- Photometric Diode Array ) was achieved, with their result deviations less than 8% and 13% for aminoglycoside and glycopeptide antibiotics, respectively.


Assuntos
Antibacterianos , Eletroforese Capilar/métodos , Aminoglicosídeos/análise , Aminoglicosídeos/química , Aminoglicosídeos/normas , Antibacterianos/análise , Antibacterianos/química , Antibacterianos/normas , Condutividade Elétrica , Eletroforese Capilar/economia , Eletroforese Capilar/instrumentação , Desenho de Equipamento , Glicopeptídeos/análise , Glicopeptídeos/química , Glicopeptídeos/normas , Limite de Detecção , Modelos Lineares , Controle de Qualidade , Reprodutibilidade dos Testes , Vietnã
18.
Nature ; 511(7510): 428-34, 2014 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-25043047

RESUMO

Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer.


Assuntos
Proteínas de Ligação a DNA/genética , Elementos Facilitadores Genéticos/genética , Variação Estrutural do Genoma/genética , Meduloblastoma/genética , Oncogenes/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Fatores de Transcrição/genética , Animais , Criança , Cromossomos Humanos Par 9/genética , Proteínas de Ligação a DNA/metabolismo , Humanos , Meduloblastoma/classificação , Meduloblastoma/patologia , Camundongos , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Repressoras/metabolismo , Fatores de Transcrição/metabolismo
19.
Molecules ; 25(10)2020 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-32414012

RESUMO

This work presents a new dual-purpose detector for photometric and conductivity measurements in flow-based analysis. The photometric detector is a paired emitter-detector diode (PEDD) device, whilst the conductivity detection employs a capacitively coupled contactless conductivity detector (C4D). The flow-through detection cell is a rectangular acrylic block (ca. 2 × 2 × 1.5 cm) with cylindrical channels in Z-configuration. For the PEDD detector, the LED light source and detector are installed inside the acrylic block. The two electrodes of the C4D are silver conducting ink painted on the PEEK inlet and outlet tubing of the Z-flow cell. The dual-purpose detector is coupled with a sequential injection analysis (SIA) system for simultaneous detection of the absorbance of the orange dye and conductivity of the dissolved oral rehydration salt powder. The detector was also used for sequential measurements of creatinine and the conductivity of human urine samples. The creatinine analysis is based on colorimetric detection of the Jaffé reaction using the PEDD detector, and the conductivity of the urine, as measured by the C4D detector, is expressed in millisiemens (mS cm-1).


Assuntos
Condutividade Elétrica , Análise de Injeção de Fluxo , Colorimetria
20.
Electrophoresis ; 40(1): 124-139, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30010203

RESUMO

The publications concerning capacitively coupled contactless conductivity detection for the 2-year period from mid-2016 to mid-2018 are covered in this update to the earlier reviews of the series. Relatively few reports on fundamental investigations or new designs have appeared in the literature in this time interval, but the development of new applications with the detection method has continued strongly. Most often, contactless conductivity measurements have been employed for the detection of inorganic or small organic ions in conventional capillary electrophoresis, less often in microchip electrophoresis. A number of other uses, such as detection in chromatography or the gauging of bubbles in streams have also been reported.


Assuntos
Eletroforese Capilar , Biomarcadores/análise , Condutividade Elétrica , Eletroforese em Microchip , Análise de Alimentos , Humanos
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