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1.
Cell ; 185(20): 3643-3645, 2022 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-36179663

RESUMO

Retrotransposons are selfish genetic elements that encode an enzyme, reverse transcriptase (RT), which converts the element-encoded RNA into DNA prior to or during genomic integration. New studies provide compelling evidence that a bacterial group II intron-like RT has adapted enzymatic activities associated with RTs to function in host DNA repair.


Assuntos
DNA Polimerase Dirigida por RNA , Retroelementos , Reparo do DNA , Elementos de DNA Transponíveis/genética , Íntrons , RNA , DNA Polimerase Dirigida por RNA/genética , DNA Polimerase Dirigida por RNA/metabolismo
2.
Cell ; 177(4): 837-851.e28, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-30955886

RESUMO

L1 retrotransposon-derived sequences comprise approximately 17% of the human genome. Darwinian selective pressures alter L1 genomic distributions during evolution, confounding the ability to determine initial L1 integration preferences. Here, we generated high-confidence datasets of greater than 88,000 engineered L1 insertions in human cell lines that act as proxies for cells that accommodate retrotransposition in vivo. Comparing these insertions to a null model, in which L1 endonuclease activity is the sole determinant dictating L1 integration preferences, demonstrated that L1 insertions are not significantly enriched in genes, transcribed regions, or open chromatin. By comparison, we provide compelling evidence that the L1 endonuclease disproportionately cleaves predominant lagging strand DNA replication templates, while lagging strand 3'-hydroxyl groups may prime endonuclease-independent L1 retrotransposition in a Fanconi anemia cell line. Thus, acquisition of an endonuclease domain, in conjunction with the ability to integrate into replicating DNA, allowed L1 to become an autonomous, interspersed retrotransposon.


Assuntos
Elementos Nucleotídeos Longos e Dispersos/genética , Retroelementos/genética , Linhagem Celular , Endonucleases/genética , Endonucleases/metabolismo , Genoma Humano/genética , Estudo de Associação Genômica Ampla/métodos , Genômica , Células HeLa , Humanos , Mutagênese Insercional/genética
3.
Nucleic Acids Res ; 51(D1): D1276-D1287, 2023 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-36484092

RESUMO

DrugCentral monitors new drug approvals and standardizes drug information. The current update contains 285 drugs (131 for human use). New additions include: (i) the integration of veterinary drugs (154 for animal use only), (ii) the addition of 66 documented off-label uses and iii) the identification of adverse drug events from pharmacovigilance data for pediatric and geriatric patients. Additional enhancements include chemical substructure searching using SMILES and 'Target Cards' based on UniProt accession codes. Statistics of interests include the following: (i) 60% of the covered drugs are on-market drugs with expired patent and exclusivity coverage, 17% are off-market, and 23% are on-market drugs with active patents and exclusivity coverage; (ii) 59% of the drugs are oral, 33% are parenteral and 18% topical, at the level of the active ingredients; (iii) only 3% of all drugs are for animal use only; however, 61% of the veterinary drugs are also approved for human use; (iv) dogs, cats and horses are by far the most represented target species for veterinary drugs; (v) the physicochemical property profile of animal drugs is very similar to that of human drugs. Use cases include azaperone, the only sedative approved for swine, and ruxolitinib, a Janus kinase inhibitor.


Assuntos
Aprovação de Drogas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Drogas Veterinárias , Animais , Humanos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/veterinária , Drogas Veterinárias/administração & dosagem , Drogas Veterinárias/efeitos adversos , Uso Off-Label/veterinária
4.
EMBO Rep ; 23(4): e53477, 2022 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-35166010

RESUMO

The vacuole/lysosome plays essential roles in the growth and proliferation of many eukaryotic cells via the activation of target of rapamycin complex 1 (TORC1). Moreover, the yeast vacuole/lysosome is necessary for progression of the cell division cycle, in part via signaling through the TORC1 pathway. Here, we show that an essential cyclin-dependent kinase, Bur1, plays a critical role in cell cycle progression in cooperation with TORC1. A mutation in BUR1 combined with a defect in vacuole inheritance shows a synthetic growth defect. Importantly, the double mutant, as well as a bur1-267 mutant on its own, has a severe defect in cell cycle progression from G1 phase. In further support that BUR1 functions with TORC1, mutation of bur1 alone results in high sensitivity to rapamycin, a TORC1 inhibitor. Mechanistic insight for Bur1 function comes from the findings that Bur1 directly phosphorylates Sch9, a target of TORC1, and that both Bur1 and TORC1 are required for the activation of Sch9. Together, these discoveries suggest that multiple signals converge on Sch9 to promote cell cycle progression.


Assuntos
Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Vacúolos , Ciclo Celular/genética , Quinases Ciclina-Dependentes/genética , Quinases Ciclina-Dependentes/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Fatores de Transcrição , Vacúolos/metabolismo
5.
Acta Neurochir (Wien) ; 166(1): 227, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38780668

RESUMO

PURPOSE: As a first step towards developing a core outcome set (COS) for sciatic neuropathy, the goal of the current study was to perform a systematic review of the literature to identify outcome measures that have been previously reported in studies on sciatic neuropathy. METHODS: A systematic review of the literature from 2000-2024 was performed utilizing PubMed and Medical Subject Headings (MeSH). Identified articles were screened according to study inclusion/exclusion criteria. Outcome measures reported in each included study were recorded and categorized into motor, sensory, pain, patient-reported outcomes, electrodiagnostic outcomes, imaging outcomes, and composite outcomes. Descriptive statistics were performed. RESULTS: A total of 1586 articles were initially identified, and 31 articles met criteria for inclusion and underwent analysis. The most common outcome domain was pain. A pain outcome was reported in 17 (63%) studies. A motor outcome was reported in 10 (37%) studies; 6 (22%) reported a sensory outcome; 1 (4%) reported a composite outcome; 4 (15%) reported an electrodiagnostic outcome; 5 (19%) reported a patient-reported outcome; 3 (11%) reported an imaging outcome. Across the included studies, 21 unique outcomes were reported. CONCLUSIONS: We have identified the outcome measures that have previously been utilized in studies on sciatic neuropathy. Previously used outcome measures fell into seven domains: motor outcomes, sensory outcomes, pain outcomes, patient-reported outcomes, electrodiagnostic outcomes, imaging outcomes, and composite outcomes. Pain outcomes were most commonly used across the included studies.


Assuntos
Neuropatia Ciática , Humanos , Avaliação de Resultados em Cuidados de Saúde , Medidas de Resultados Relatados pelo Paciente
6.
Molecules ; 29(2)2024 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-38257401

RESUMO

The small-molecule iododiflunisal (IDIF) is a transthyretin (TTR) tetramer stabilizer and acts as a chaperone of the TTR-Amyloid beta interaction. Oral administration of IDIF improves Alzheimer's Disease (AD)-like pathology in mice, although the mechanism of action and pharmacokinetics remain unknown. Radiolabeling IDIF with positron or gamma emitters may aid in the in vivo evaluation of IDIF using non-invasive nuclear imaging techniques. In this work, we report an isotopic exchange reaction to obtain IDIF radiolabeled with 18F. [19F/18F]exchange reaction over IDIF in dimethyl sulfoxide at 160 °C resulted in the formation of [18F]IDIF in 7 ± 3% radiochemical yield in a 20 min reaction time, with a final radiochemical purity of >99%. Biodistribution studies after intravenous administration of [18F]IDIF in wild-type mice using positron emission tomography (PET) imaging showed capacity to cross the blood-brain barrier (ca. 1% of injected dose per gram of tissue in the brain at t > 10 min post administration), rapid accumulation in the liver, long circulation time, and progressive elimination via urine. Our results open opportunities for future studies in larger animal species or human subjects.


Assuntos
Doença de Alzheimer , Diflunisal/análogos & derivados , Humanos , Animais , Camundongos , Preparações Farmacêuticas , Distribuição Tecidual , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/tratamento farmacológico , Pré-Albumina , Peptídeos beta-Amiloides , Excipientes
7.
RNA ; 2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33975916

RESUMO

Pre-mRNA splicing is carried out by the spliceosome and involves splice site recognition, removal of introns, and ligation of exons. Components of the spliceosome have been shown to interact with the elongating RNA polymerase II (RNAPII) which is thought to allow splicing to occur concurrently with transcription. However, little is known about the regulation and efficiency of co-transcriptional splicing in human cells. In this study, we used Bru-seq and BruChase-seq to determine the co-transcriptional splicing efficiencies of 17,000 introns expressed across 6 human cell lines. We found that less than half of all introns across these 6 cell lines were co-transcriptionally spliced. Splicing efficiencies for individual introns showed variations across cell lines, suggesting that splicing may be regulated in a cell-type specific manner. Moreover, the splicing efficiency of introns varied within genes. The efficiency of co-transcriptional splicing did not correlate with gene length, intron position, splice site strengths, or the intron/neighboring exons GC content. However, we identified binding signals from multiple RNA binding proteins (RBPs) that correlated with splicing efficiency, including core spliceosomal machinery components-such as SF3B4, U2AF1 and U2AF2 showing higher binding signals in poorly spliced introns. In addition, multiple RBPs, such as BUD13, PUM1 and SND1, showed preferential binding in exons that flank introns with high splicing efficiencies. The nascent RNA splicing patterns presented here across multiple cell types add to our understanding of the complexity in RNA splicing, wherein RNA-binding proteins may play important roles in determining splicing outcomes in a cell type- and intron-specific manner.

8.
J Pediatr ; 257: 113332, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36708874

RESUMO

OBJECTIVES: To define the baseline characteristics of long-term tube-fed (TF) single ventricle patients, investigate associations between long-term enteral tube feeding and growth, and determine associations with long-term outcomes after Fontan procedure. STUDY DESIGN: We performed a retrospective cohort study of patients in the Australia and New Zealand Fontan Registry undergoing treatment at the Royal Children's Hospital, the Children's Hospital at Westmead, Royal Melbourne Hospital, and Royal Prince Alfred Hospital from 1981 to 2018. Patients were defined as TF or non-tube-fed (NTF) based on enteral tube feeding at the age of 90 days. Feeding groups were compared regarding body mass index (BMI) trajectory, BMI at last follow-up, and long-term incidence of severe Fontan failure. RESULTS: Of 390 patients (56 [14%] TF, 334 [86%] NTF), TF was associated with right ventricular dominance, hypoplastic left heart syndrome, Norwood procedure, increased procedures prior to Fontan, extracardiac conduit Fontan, Fontan fenestration, and atrioventricular valve repair/replacement. TF patients were less likely to be in the higher compared with lowest 0-6 month BMI trajectory (P < .01; P = .03), had lower 6 month weight-for-age z-scores (P < .01) and length-for-age z-scores (P = .01). TF were less likely to be overweight/obese at pediatric follow-up (hazard ratio [HR] = 0.31, 95% CI: 0.12-0.80; P = .02) and more likely to be underweight at adult follow-up (HR = 16.51; 5% CI: 2.70-101.10; P < .01). TF compared with NTF was associated with increased risk of severe Fontan failure (HR = 4.13; 95% CI = 1.65-10.31; P < .01). CONCLUSIONS: Prolonged infant enteral tube feeding is an independent marker of poor growth and adverse clinical outcomes extending long-term post-Fontan procedure.


Assuntos
Técnica de Fontan , Cardiopatias Congênitas , Síndrome do Coração Esquerdo Hipoplásico , Coração Univentricular , Adulto , Criança , Humanos , Lactente , Estudos Retrospectivos , Nutrição Enteral , Resultado do Tratamento , Síndrome do Coração Esquerdo Hipoplásico/cirurgia , Técnica de Fontan/efeitos adversos , Cardiopatias Congênitas/cirurgia , Cardiopatias Congênitas/etiologia
9.
World J Urol ; 41(2): 463-469, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36602577

RESUMO

BACKGROUND: To determine the utility of diagnostic 18F-DCPyL PSMA-PET/CT to aid management of men with highly suspicious multiparametric MRI prostate (PIRAD 4-5 lesions) and discrepant negative prostate biopsy. METHODS: A multicentre prospective consecutive case series was conducted (2018-2021), recruiting men with prior mpMRI prostate PIRADS 4-5 lesions and negative prostate biopsy. All men had 18F-DCPyL PSMA-PET/CT with subsequent management based on the concordance between MRI and PET: (1) Concordant lesions were biopsied using in-bore MRI targeting; (2) PSMA-PET/CT avidity without MRI correlate were biopsied using cognitive/software targeting with ultrasound guidance and (3) Patients with negative PET/CT were returned to standard of care follow-up. RESULTS: 29 patients were recruited with 48% (n = 14) having concordant MRI/PET abnormalities. MRI targeted biopsy found prostate cancer in six patients, with grade groups GG3 (n = 1), GG2 (n = 1), GG1 (n = 4) found. Of the 20 men who PSMA-PET/CT avidity and biopsy, analysis showed higher SUVmax (20.1 vs 6.8, p = 0.036) predicted prostate cancer. Of patients who had PSMA-PET avidity without MRI correlate, and those with no PSMA-PET avidity, only one patient was subsequently found to have prostate cancer (GG1). The study is limited by small size and short follow-up of 17 months (IQR 12.5-29.9). CONCLUSIONS: PSMA-PET/CT is useful in this group of men but requires further investigation. Avidity (higher SUVmax) that correlates to the mpMRI prostate lesion should be considered for targeted biopsy.


Assuntos
Próstata , Neoplasias da Próstata , Masculino , Humanos , Próstata/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Estudos Prospectivos , Compostos Radiofarmacêuticos , Imageamento por Ressonância Magnética , Neoplasias da Próstata/patologia , Biópsia
10.
Nucleic Acids Res ; 49(22): 12607-12621, 2021 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-34263309

RESUMO

Resection of the 5'-terminated strand at DNA double-strand breaks (DSBs) is the critical regulated step in the transition to homologous recombination. Recent studies have described a multi-step model of DSB resection where endonucleolytic cleavage mediated by Mre11 and Sae2 leads to further degradation mediated by redundant pathways catalyzed by Exo1 and Sgs1/Dna2. These models have not been well tested at mitotic DSBs in vivo because most methods used to monitor resection cannot precisely map early cleavage events. Here we report resection monitoring with high-throughput sequencing using molecular identifiers, allowing exact counting of cleaved 5' ends at base resolution. Mutant strains, including exo1Δ, mre11-H125N and exo1Δ sgs1Δ, revealed a major Mre11-dependent cleavage position 60-70 bp from the DSB end whose exact position depended on local sequence. They further revealed an Exo1-dependent pause point approximately 200 bp from the DSB. Suppressing resection extension in exo1Δ sgs1Δ yeast exposed a footprint of regions where cleavage was restricted within 119 bp of the DSB. These results provide detailed in vivo views of prevailing models of DSB resection and extend them to show the combined influence of sequence specificity and access restrictions on Mre11 and Exo1 nucleases.


Assuntos
Quebras de DNA de Cadeia Dupla , Exodesoxirribonucleases/metabolismo , Proteínas Fúngicas/metabolismo , Proteína Homóloga a MRE11/metabolismo , Mitose/genética , Reparo de DNA por Recombinação , Alelos , Sequência de Bases , DNA/química , Reparo do DNA por Junção de Extremidades , Exodesoxirribonucleases/genética , Proteínas Fúngicas/fisiologia , Deleção de Genes , Proteína Homóloga a MRE11/fisiologia , RecQ Helicases/genética , Saccharomycetales/enzimologia , Saccharomycetales/genética
11.
Nucleic Acids Res ; 49(13): 7507-7524, 2021 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-34181717

RESUMO

Impaired replication progression leads to de novo copy number variant (CNV) formation at common fragile sites (CFSs). We previously showed that these hotspots for genome instability reside in late-replicating domains associated with large transcribed genes and provided indirect evidence that transcription is a factor in their instability. Here, we compared aphidicolin (APH)-induced CNV and CFS frequency between wild-type and isogenic cells in which FHIT gene transcription was ablated by promoter deletion. Two promoter-deletion cell lines showed reduced or absent CNV formation and CFS expression at FHIT despite continued instability at the NLGN1 control locus. APH treatment led to critical replication delays that remained unresolved in G2/M in the body of many, but not all, large transcribed genes, an effect that was reversed at FHIT by the promoter deletion. Altering RNase H1 expression did not change CNV induction frequency and DRIP-seq showed a paucity of R-loop formation in the central regions of large genes, suggesting that R-loops are not the primary mediator of the transcription effect. These results demonstrate that large gene transcription is a determining factor in replication stress-induced genomic instability and support models that CNV hotspots mainly result from the transcription-dependent passage of unreplicated DNA into mitosis.


Assuntos
Hidrolases Anidrido Ácido/genética , Variações do Número de Cópias de DNA , Replicação do DNA , Proteínas de Neoplasias/genética , Transcrição Gênica , Hidrolases Anidrido Ácido/biossíntese , Animais , Afidicolina/farmacologia , Linhagem Celular , Sítios Frágeis do Cromossomo , Loci Gênicos , Humanos , Camundongos , Mutação , Proteínas de Neoplasias/biossíntese , Regiões Promotoras Genéticas , Estruturas R-Loop , Ribonuclease H/metabolismo , Estresse Fisiológico
12.
Nucleic Acids Res ; 49(D1): D1160-D1169, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33151287

RESUMO

DrugCentral is a public resource (http://drugcentral.org) that serves the scientific community by providing up-to-date drug information, as described in previous papers. The current release includes 109 newly approved (October 2018 through March 2020) active pharmaceutical ingredients in the US, Europe, Japan and other countries; and two molecular entities (e.g. mefuparib) of interest for COVID19. New additions include a set of pharmacokinetic properties for ∼1000 drugs, and a sex-based separation of side effects, processed from FAERS (FDA Adverse Event Reporting System); as well as a drug repositioning prioritization scheme based on the market availability and intellectual property rights forFDA approved drugs. In the context of the COVID19 pandemic, we also incorporated REDIAL-2020, a machine learning platform that estimates anti-SARS-CoV-2 activities, as well as the 'drugs in news' feature offers a brief enumeration of the most interesting drugs at the present moment. The full database dump and data files are available for download from the DrugCentral web portal.


Assuntos
Antivirais/uso terapêutico , Tratamento Farmacológico da COVID-19 , Bases de Dados de Produtos Farmacêuticos/estatística & dados numéricos , Aprovação de Drogas/estatística & dados numéricos , Descoberta de Drogas/estatística & dados numéricos , Reposicionamento de Medicamentos/estatística & dados numéricos , SARS-CoV-2/efeitos dos fármacos , Antivirais/efeitos adversos , Antivirais/farmacocinética , COVID-19/epidemiologia , COVID-19/virologia , Aprovação de Drogas/métodos , Descoberta de Drogas/métodos , Reposicionamento de Medicamentos/métodos , Epidemias , Europa (Continente) , Humanos , Armazenamento e Recuperação da Informação/métodos , Internet , Japão , SARS-CoV-2/fisiologia , Estados Unidos
13.
Neurosurg Focus ; 54(2): E3, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36724520

RESUMO

OBJECTIVE: To the authors' knowledge, no data have been reported on dopamine fluctuations on subsecond timescales in humans with alcohol use disorder (AUD). In this study, dopamine release was monitored in 2 patients with and 2 without a history of AUD during a "sure bet or gamble" (SBORG) decision-making task to begin to characterize how subsecond dopamine responses to counterfactual information, related to psychological notions of regret and relief, in AUD may be altered. METHODS: Measurements of extracellular dopamine levels were made once every 100 msec using human voltammetric methods. Measurements were made in the caudate during deep brain stimulation electrode implantation surgeries (for treatment of movement disorders) in patients who did (AUD, n = 2) or did not (non-AUD, n = 2) have a history of AUD. Participants performed an SBORG decision-making task in which they made choices between sure bets and 50%-chance monetary gamble outcomes. RESULTS: Fast changes were found in dopamine levels that appear to be modulated by "what could have been" and by patients' AUD status. Positive counterfactual prediction errors (related to relief) differentiated patients with versus without a history of AUD. CONCLUSIONS: Dopaminergic encoding of counterfactual information appears to differ between patients with and without AUD. The current study has a major limitation of a limited sample size, but these data provide a rare insight into dopaminergic physiology during real-time decision-making in humans with an addiction disorder. The authors hope future work will expand the sample size and determine the generalizability of the current results.


Assuntos
Alcoolismo , Humanos , Alcoolismo/terapia , Dopamina , Emoções
14.
Acta Neurochir (Wien) ; 165(9): 2597-2604, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37587319

RESUMO

BACKGROUND: There is a strong need for the development of core outcome sets (COS) across nerve surgery to allow for improved data synthesis, meta-analyses, and reporting consistency. Development of a core outcome set typically starts with assessing the literature for previously reported outcome measures. Common peroneal neuropathy (CPN) is the most common compressive mononeuropathy of the lower extremity and can result in pain, motor, and sensory deficits. A COS for COmmon PEroneal neuropathy (COS-COPE) is needed to improve future study design and comparison and synthesis of data. The goal of the current study was to assess the literature for outcomes reported in studies on CPN as the first step in the development of a COS. METHODS: A systematic review of the literature from 2000 to 2023 was performed utilizing PubMed and Medical Subject Headings (MeSH). Identified articles were screened according to study inclusion/exclusion criteria. Outcome measures reported in each included study were recorded and categorized into motor, sensory, pain, composite foot/ankle score, electrodiagnostics, function/disability patient-reported outcome (PRO), psychological, or other outcomes. Descriptive statistics were performed. RESULTS: A total of 31 articles met criteria for inclusion. A motor outcome was reported in 26 (83.9%) studies; 12 (38.7%) reported a sensory outcome; 8 (25.8%) reported a pain outcome; 4 (12.9%) reported a composite foot/ankle score; 3 (9.7%) reported electrodiagnostics; 1 (3.2%) reported a function/disability PRO; 1 (3.2%) reported a psychological outcome; 2 (6.5%) reported an imaging outcome; 3 (9.7%) reported other outcomes. Across the studies, 29 distinct outcome measures were reported. CONCLUSIONS: The outcomes reported in studies on CPN are varied and inconsistent. It is likely that a combination of motor, sensory, pain, and functional outcomes will be needed in a COS to best study CPN. These data will serve as a baseline for the ultimate development of the COS-COPE.


Assuntos
Neuropatias Fibulares , Humanos , Neuropatias Fibulares/diagnóstico , Neuropatias Fibulares/cirurgia , Extremidade Inferior , Procedimentos Neurocirúrgicos , Dor , Medidas de Resultados Relatados pelo Paciente
15.
Acta Neurochir (Wien) ; 165(11): 3539-3547, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37684428

RESUMO

Since the initial description of intraneural (IN) perineurioma in 1964, advances in the understanding of the clinical presentation, diagnostic imaging, pathologic features, and genetic underpinnings have changed how this pathology is managed. IN perineuriomas are rare, benign peripheral nerve sheath tumors, most frequently coming to clinical attention when patients present with painless, progressive weakness or sensory loss in adolescence or young adulthood. The gold standard of diagnosis has traditionally been with targeted tissue biopsy demonstrating "pseudo-onion bulb" formation with positive epithelial membrane antigen (EMA) staining. However, modern magnetic resonance imaging is allowing some patients to forgo biopsy. Recent genetic studies of IN perineuriomas have demonstrated common TRAF7 point mutations and rare NF2 mutations, which may present targets for diagnosis or therapy in the future. Current advances have allowed for us to provide improved patient counseling with informed understanding for various clinical scenarios. With the workup and diagnosis now clearly defined, the next frontier is for improving the lives of patients with IN perineuriomas through the interaction between restoration of functional deficits and advances in our understanding of the genetics of this entity.


Assuntos
Neoplasias dos Nervos Cranianos , Neoplasias de Bainha Neural , Neoplasias do Sistema Nervoso Periférico , Adolescente , Humanos , Adulto Jovem , Adulto , Neoplasias de Bainha Neural/diagnóstico , Neoplasias de Bainha Neural/genética , Neoplasias de Bainha Neural/cirurgia , Neoplasias do Sistema Nervoso Periférico/diagnóstico por imagem , Neoplasias do Sistema Nervoso Periférico/genética , Imageamento por Ressonância Magnética , Mucina-1
16.
Metabolomics ; 18(8): 64, 2022 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-35917032

RESUMO

INTRODUCTION: Flow infusion electrospray high resolution mass spectrometry (FIE-HRMS) fingerprinting produces complex, high dimensional data sets which require specialist in-silico software tools to process the data prior to analysis. OBJECTIVES: Present spectral binning as a pragmatic approach to post-acquisition procession of FIE-HRMS metabolome fingerprinting data. METHODS: A spectral binning approach was developed that included the elimination of single scan m/z events, the binning of spectra and the averaging of spectra across the infusion profile. The modal accurate m/z was then extracted for each bin. This approach was assessed using four different biological matrices and a mix of 31 known chemical standards analysed by FIE-HRMS using an Exactive Orbitrap. Bin purity and centrality metrics were developed to objectively assess the distribution and position of accurate m/z within an individual bin respectively. RESULTS: The optimal spectral binning width was found to be 0.01 amu. 80.8% of the extracted accurate m/z matched to predicted ionisation products of the chemical standards mix were found to have an error of below 3 ppm. The open-source R package binneR was developed as a user friendly implementation of the approach. This was able to process 100 data files using 4 Central Processing Units (CPU) workers in only 55 seconds with a maximum memory usage of 1.36 GB. CONCLUSION: Spectral binning is a fast and robust method for the post-acquisition processing of FIE-HRMS data. The open-source R package binneR allows users to efficiently process data from FIE-HRMS experiments with the resources available on a standard desktop computer.


Assuntos
Metaboloma , Metabolômica , Humanos , Espectrometria de Massas/métodos , Metabolômica/métodos , Software
17.
Vox Sang ; 117(11): 1323-1326, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36102159

RESUMO

BACKGROUND AND OBJECTIVES: The field of transfusion medicine started out with whole blood transfusion to treat severe anaemia and other deficiencies, and then transitioned to component therapy, largely leaving the practice, and experiences, of whole blood transfusions behind. Currently, the field is circling back and whole blood is gaining ground as an alternative to massive transfusion protocols. MATERIALS AND METHODS: Herein we describe a severely anaemic paroxysmal nocturnal haemoglobinuria (PNH) patient initially suspected of suffering from renal haemorrhage, receiving a standard low-titre group O whole blood transfusion during pre-hospital transportation. RESULTS: Following the transfusion, the patient suffered a clinically unmistakable haemolytic transfusion reaction requiring supportive treatment in the intensive care unit. Clinical observations are consistent with an acute haemolytic reaction. The haemolysis was likely due to minor incompatibility between the plasma from the transfused whole blood and the patient's PNH red cells. Recovery was uneventful. CONCLUSION: This revealed an unappreciated contraindication to minor incompatible whole blood transfusion, and prompted a discussion on the distinction between whole blood and erythrocyte concentrates, the different indications for use and the importance of emphasizing these differences. It also calls attention to patient groups where minor incompatibility can be of major importance.


Assuntos
Hemoglobinúria Paroxística , Reação Transfusional , Humanos , Hemoglobinúria Paroxística/tratamento farmacológico , Transfusão de Sangue , Incompatibilidade de Grupos Sanguíneos , Sistema ABO de Grupos Sanguíneos , Hemólise
18.
Inorg Chem ; 61(3): 1456-1470, 2022 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-34995063

RESUMO

Indolo[2,3-d]benzazepines (indololatonduines) are rarely discussed in the literature. In this project, we prepared a series of novel indololatonduine derivatives and their RuII and OsII complexes and investigated their microtubule-targeting properties in comparison with paclitaxel and colchicine. Compounds were fully characterized by spectroscopic techniques (1H NMR and UV-vis), ESI mass-spectrometry, and X-ray crystallography, and their purity was confirmed by elemental analysis. The stabilities of the compounds in DMSO and water were confirmed by 1H and 13C NMR and UV-vis spectroscopy. Novel indololatonduines demonstrated anticancer activity in vitro in a low micromolar concentration range, while their coordination to metal centers resulted in a decrease of cytotoxicity. The preliminary in vivo activity of the RuII complex was investigated. Fluorescence staining and in vitro tubulin polymerization assays revealed the prepared compounds to have excellent microtubule-destabilizing activities, even more potent than the well-known microtubule-destabilizing agent colchicine.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Indóis/farmacologia , Microtúbulos/efeitos dos fármacos , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Compostos Heterocíclicos com 3 Anéis/química , Humanos , Indóis/química , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Nus , Microscopia de Fluorescência , Microtúbulos/metabolismo , Modelos Moleculares , Estrutura Molecular , Polimerização/efeitos dos fármacos , Tubulina (Proteína)/metabolismo , Células Tumorais Cultivadas
19.
Proc Natl Acad Sci U S A ; 116(19): 9481-9490, 2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-31019070

RESUMO

DNA double-strand breaks (DSBs) are serious genomic insults that can lead to chromosomal rearrangements if repaired incorrectly. To gain insight into the nuclear mechanisms contributing to these rearrangements, we developed an assay in yeast to measure cis (same site) vs. trans (different site) repair for the majority process of precise nonhomologous end joining (NHEJ). In the assay, the HO endonuclease gene is placed between two HO cut sites such that HO expression is self-terminated upon induction. We further placed an additional cut site in various genomic loci such that NHEJ in trans led to expression of a LEU2 reporter gene. Consistent with prior reports, cis NHEJ was more efficient than trans NHEJ. However, unlike homologous recombination, where spatial distance between a single DSB and donor locus was previously shown to correlate with repair efficiency, trans NHEJ frequency remained essentially constant regardless of the position of the two DSB loci, even when they were on the same chromosome or when two trans repair events were put in competition. Repair of similar DSBs via single-strand annealing of short terminal direct repeats showed substantially higher repair efficiency and trans repair frequency, but still without a strong correlation of trans repair to genomic position. Our results support a model in which yeast cells mobilize, and perhaps compartmentalize, multiple DSBs in a manner that no longer reflects the predamage position of two broken loci.


Assuntos
Quebras de DNA de Cadeia Dupla , Reparo do DNA por Junção de Extremidades/fisiologia , Regulação Fúngica da Expressão Gênica/fisiologia , Loci Gênicos/fisiologia , Genoma Fúngico/fisiologia , Saccharomyces cerevisiae , 3-Isopropilmalato Desidrogenase/biossíntese , 3-Isopropilmalato Desidrogenase/genética , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/biossíntese , Proteínas de Saccharomyces cerevisiae/genética
20.
Acta Neurochir (Wien) ; 164(5): 1337-1345, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-34993620

RESUMO

PURPOSE: There is a strong need for a set of consensus outcomes to be utilized for future studies on cubital tunnel syndrome. The goal was to assess the outcome measures utilized in the cubital tunnel syndrome literature as a way of measuring popularity/acceptability and then to perform a literature review for the most commonly used outcomes. METHODS: A literature search was performed using the pubmed.gov database and Medical Subject Headings (MeSH). For each article, the following data were abstracted: study type, motor outcome(s), sensory outcome(s), composite outcome(s), patient-reported outcome (PRO) metric(s), pain outcome(s), psychological outcome(s), electrodiagnostic outcome(s), and any other outcomes that were used. RESULTS: A composite outcome was reported in 52/85 (61%) studies, with the modified Bishop score (27/85; 32%) most common. A motor outcome was reported in 44/85 (52%) studies, with dynamometry (38/85; 45%) most common. The majority of studies (55%) did not report a sensory outcome. The majority of studies (52%) did not report a PRO. A specific pain outcome was reported in the minority (23/85; 27%), with the visual analogue scale (VAS) (22/85; 26%) most common. Pre- and postoperative electrodiagnostic results were presented in 22/85 studies (26%). DISCUSSION: Understanding current clinical practice and historical outcomes reporting provides a foundation for discussion regarding the development of a core outcome set for cubital tunnel syndrome. We hope that the data provided in the current study will stoke a discussion that will culminate in a consensus statement for research reporting in cubital tunnel syndrome studies.


Assuntos
Síndrome do Túnel Ulnar , Síndrome do Túnel Ulnar/diagnóstico , Síndrome do Túnel Ulnar/cirurgia , Descompressão Cirúrgica/métodos , Humanos , Avaliação de Resultados em Cuidados de Saúde , Dor/cirurgia , Nervo Ulnar/cirurgia
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