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1.
Cell ; 187(7): 1636-1650, 2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38552611

RESUMO

The precision oncology paradigm challenges the feasibility and data generalizability of traditional clinical trials. Consequently, an unmet need exists for practical approaches to test many subgroups, evaluate real-world drug value, and gather comprehensive, accessible datasets to validate novel biomarkers. Real-world data (RWD) are increasingly recognized to have the potential to fill this gap in research methodology. Established applications of RWD include informing disease epidemiology, pharmacovigilance, and healthcare quality assessment. Currently, concerns regarding RWD quality and comprehensiveness, privacy, and biases hamper their broader application. Nonetheless, RWD may play a pivotal role in supplementing clinical trials, enabling conditional reimbursement and accelerated drug access, and innovating trial conduct. Moreover, purpose-built RWD repositories may support the extension or refinement of drug indications and facilitate the discovery and validation of new biomarkers. This perspective explores the potential of leveraging RWD to advance oncology, highlights its benefits and challenges, and suggests a path forward in this evolving field.


Assuntos
Neoplasias , Humanos , Medicina de Precisão , Oncologia , Projetos de Pesquisa , Biomarcadores
2.
Cell ; 180(1): 9-14, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31951522

RESUMO

This commentary introduces a new clinical trial construct, the Master Observational Trial (MOT), which hybridizes the power of molecularly based master interventional protocols with the breadth of real-world data. The MOT provides a clinical venue to allow molecular medicine to rapidly advance, answers questions that traditional interventional trials generally do not address, and seamlessly integrates with interventional trials in both diagnostic and therapeutic arenas. The result is a more comprehensive data collection ecosystem in precision medicine.


Assuntos
Estudos Observacionais como Assunto/métodos , Medicina de Precisão/métodos , Projetos de Pesquisa/normas , Big Data , Protocolos de Ensaio Clínico como Assunto , Humanos , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Estudos Observacionais como Assunto/normas
3.
Cell ; 168(6): 1126-1134.e9, 2017 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-28262353

RESUMO

Phosphate is essential for all living systems, serving as a building block of genetic and metabolic machinery. However, it is unclear how phosphate could have assumed these central roles on primordial Earth, given its poor geochemical accessibility. We used systems biology approaches to explore the alternative hypothesis that a protometabolism could have emerged prior to the incorporation of phosphate. Surprisingly, we identified a cryptic phosphate-independent core metabolism producible from simple prebiotic compounds. This network is predicted to support the biosynthesis of a broad category of key biomolecules. Its enrichment for enzymes utilizing iron-sulfur clusters, and the fact that thermodynamic bottlenecks are more readily overcome by thioester rather than phosphate couplings, suggest that this network may constitute a "metabolic fossil" of an early phosphate-free nonenzymatic biochemistry. Our results corroborate and expand previous proposals that a putative thioester-based metabolism could have predated the incorporation of phosphate and an RNA-based genetic system. PAPERCLIP.


Assuntos
Simulação por Computador , Redes e Vias Metabólicas , Fosfatos/metabolismo , Nucleotídeos de Adenina/química , Algoritmos , Coenzima A , Coenzimas , Origem da Vida , Fosfatos/química , Termodinâmica
4.
CA Cancer J Clin ; 72(3): 287-300, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-34964981

RESUMO

Generating evidence on the use, effectiveness, and safety of new cancer therapies is a priority for researchers, health care providers, payers, and regulators given the rapid pace of change in cancer diagnosis and treatments. The use of real-world data (RWD) is integral to understanding the utilization patterns and outcomes of these new treatments among patients with cancer who are treated in clinical practice and community settings. An initial step in the use of RWD is careful study design to assess the suitability of an RWD source. This pivotal process can be guided by using a conceptual model that encourages predesign conceptualization. The primary types of RWD included are electronic health records, administrative claims data, cancer registries, and specialty data providers and networks. Careful consideration of each data type is necessary because they are collected for a specific purpose, capturing a set of data elements within a certain population for that purpose, and they vary by population coverage and longitudinality. In this review, the authors provide a high-level assessment of the strengths and limitations of each data category to inform data source selection appropriate to the study question. Overall, the development and accessibility of RWD sources for cancer research are rapidly increasing, and the use of these data requires careful consideration of composition and utility to assess important questions in understanding the use and effectiveness of new therapies.


Assuntos
Armazenamento e Recuperação da Informação , Oncologia , Registros Eletrônicos de Saúde , Humanos , Sistema de Registros , Projetos de Pesquisa
5.
Proc Natl Acad Sci U S A ; 121(35): e2410206121, 2024 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-39178230

RESUMO

Coded ribosomal peptide synthesis could not have evolved unless its sequence and amino acid-specific aminoacylated tRNA substrates already existed. We therefore wondered whether aminoacylated RNAs might have served some primordial function prior to their role in protein synthesis. Here, we show that specific RNA sequences can be nonenzymatically aminoacylated and ligated to produce amino acid-bridged stem-loop RNAs. We used deep sequencing to identify RNAs that undergo highly efficient glycine aminoacylation followed by loop-closing ligation. The crystal structure of one such glycine-bridged RNA hairpin reveals a compact internally stabilized structure with the same eponymous T-loop architecture that is found in many noncoding RNAs, including the modern tRNA. We demonstrate that the T-loop-assisted amino acid bridging of RNA oligonucleotides enables the rapid template-free assembly of a chimeric version of an aminoacyl-RNA synthetase ribozyme. We suggest that the primordial assembly of amino acid-bridged chimeric ribozymes provides a direct and facile route for the covalent incorporation of amino acids into RNA. A greater functionality of covalently incorporated amino acids could contribute to enhanced ribozyme catalysis, providing a driving force for the evolution of sequence and amino acid-specific aminoacyl-RNA synthetase ribozymes in the RNA World. The synthesis of specifically aminoacylated RNAs, an unlikely prospect for nonenzymatic reactions but a likely one for ribozymes, could have set the stage for the subsequent evolution of coded protein synthesis.


Assuntos
Aminoacilação , RNA Catalítico , RNA Catalítico/metabolismo , RNA Catalítico/química , RNA Catalítico/genética , Conformação de Ácido Nucleico , Biossíntese Peptídica , Glicina/química , Glicina/metabolismo , RNA/química , RNA/metabolismo , RNA/genética , Peptídeos/química , Peptídeos/metabolismo , RNA de Transferência/metabolismo , RNA de Transferência/genética , RNA de Transferência/química , Biossíntese de Proteínas , Aminoacilação de RNA de Transferência , Aminoácidos/química , Aminoácidos/metabolismo
6.
Proc Natl Acad Sci U S A ; 121(6): e2318008121, 2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38306478

RESUMO

Several structured noncoding RNAs in bacteria are essential contributors to fundamental cellular processes. Thus, discoveries of additional ncRNA classes provide opportunities to uncover and explore biochemical mechanisms relevant to other major and potentially ancient processes. A candidate structured ncRNA named the "raiA motif" has been found via bioinformatic analyses in over 2,500 bacterial species. The gene coding for the RNA typically resides between the raiA and comFC genes of many species of Bacillota and Actinomycetota. Structural probing of the raiA motif RNA from the Gram-positive anaerobe Clostridium acetobutylicum confirms key features of its sophisticated secondary structure model. Expression analysis of raiA motif RNA reveals that the RNA is constitutively produced but reaches peak abundance during the transition from exponential growth to stationary phase. The raiA motif RNA becomes the fourth most abundant RNA in C. acetobutylicum, excluding ribosomal RNAs and transfer RNAs. Genetic disruption of the raiA motif RNA causes cells to exhibit substantially decreased spore formation and diminished ability to aggregate. Restoration of normal cellular function in this knock-out strain is achieved by expression of a raiA motif gene from a plasmid. These results demonstrate that raiA motif RNAs normally participate in major cell differentiation processes by operating as a trans-acting factor.


Assuntos
Clostridium acetobutylicum , Clostridium acetobutylicum/genética , RNA não Traduzido/genética , RNA não Traduzido/metabolismo , RNA/metabolismo , Bactérias/genética , RNA Ribossômico/metabolismo , RNA Bacteriano/genética , RNA Bacteriano/metabolismo
7.
Proc Natl Acad Sci U S A ; 121(38): e2407325121, 2024 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-39269776

RESUMO

The acquisition of new RNA functions through evolutionary processes was essential for the diversification of RNA-based primordial biology and its subsequent transition to modern biology. However, the mechanisms by which RNAs access new functions remain unclear. Do RNA enzymes need completely new folds to support new but related functions, or is reoptimization of the active site sufficient? What are the roles of neutral and adaptive mutations in evolutionary innovation? Here, we address these questions experimentally by focusing on the evolution of substrate specificity in RNA-catalyzed RNA assembly. We use directed in vitro evolution to show that a ligase ribozyme that uses prebiotically relevant 5'-phosphorimidazole-activated substrates can be evolved to catalyze ligation with substrates that are 5'-activated with the biologically relevant triphosphate group. Interestingly, despite catalyzing a related reaction, the new ribozyme folds into a completely new structure and exhibits promiscuity by catalyzing RNA ligation with both triphosphate and phosphorimidazole-activated substrates. Although distinct in sequence and structure, the parent phosphorimidazolide ligase and the evolved triphosphate ligase ribozymes can be connected by a series of point mutations where the intermediate sequences retain at least some ligase activity. The existence of a quasi-neutral pathway between these distinct ligase ribozymes suggests that neutral drift is sufficient to enable the acquisition of new substrate specificity, thereby providing opportunities for subsequent adaptive optimization. The transition from RNA-catalyzed RNA assembly using phosphorimidazole-activated substrates to triphosphate-activated substrates may have foreshadowed the later evolution of the protein enzymes that use monomeric triphosphates (nucleoside triphosphates, NTPs) for RNA synthesis.


Assuntos
Imidazóis , RNA Ligase (ATP) , RNA Catalítico , RNA Catalítico/metabolismo , RNA Catalítico/química , RNA Catalítico/genética , Especificidade por Substrato , Imidazóis/metabolismo , Imidazóis/química , RNA Ligase (ATP)/metabolismo , RNA Ligase (ATP)/química , RNA Ligase (ATP)/genética , Evolução Molecular , Conformação de Ácido Nucleico , Domínio Catalítico
8.
Proc Natl Acad Sci U S A ; 121(26): e2401257121, 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38889155

RESUMO

Negative or antagonistic relationships are common in human social networks, but they are less often studied than positive or friendly relationships. The existence of a capacity to have and to track antagonistic ties raises the possibility that they may serve a useful function in human groups. Here, we analyze empirical data gathered from 24,770 and 22,513 individuals in 176 rural villages in Honduras in two survey waves 2.5 y apart in order to evaluate the possible relevance of antagonistic relationships for broader network phenomena. We find that the small-world effect is more significant in a positive world with negative ties compared to an otherwise similar hypothetical positive world without them. Additionally, we observe that nodes with more negative ties tend to be located near network bridges, with lower clustering coefficients, higher betweenness centralities, and shorter average distances to other nodes in the network. Positive connections tend to have a more localized distribution, while negative connections are more globally dispersed within the networks. Analysis of the possible impact of such negative ties on dynamic processes reveals that, remarkably, negative connections can facilitate the dissemination of information (including novel information experimentally introduced into these villages) to the same degree as positive connections, and that they can also play a role in mitigating idea polarization within village networks. Antagonistic ties hold considerable importance in shaping the structure and function of social networks.


Assuntos
População Rural , Apoio Social , Humanos , Honduras , Rede Social , Masculino , Feminino , Relações Interpessoais , Análise de Rede Social
9.
Proc Natl Acad Sci U S A ; 120(3): e2212649120, 2023 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-36623193

RESUMO

The World Wide Web (WWW) empowers people in developing regions by eradicating illiteracy, supporting women, and generating economic opportunities. However, their reliance on limited bandwidth and low-end phones leaves them with a poorer browsing experience compared to privileged users across the digital divide. To evaluate the extent of this phenomenon, we sent participants to 56 cities to measure the cost of mobile data and the average page load time. We found the cost to be orders of magnitude greater, and the average page load time to be four times slower, in some locations compared to others. Analyzing how popular webpages have changed over the past years suggests that they are increasingly designed with high processing power in mind, effectively leaving the less fortunate users behind. Addressing this digital inequality through new infrastructure takes years to complete and billions of dollars to finance. A more practical solution is to make the webpages more accessible by reducing their size and optimizing their load time. To this end, we developed a solution called Lite-Web and evaluated it in the Gilgit-Baltistan province of Pakistan, demonstrating that it transforms the browsing experience of a Pakistani villager using a low-end phone to almost that of a Dubai resident using a flagship phone. A user study in two high schools in Pakistan confirms that the performance gains come at no expense to the pages' look and functionality. These findings suggest that deploying Lite-Web at scale would constitute a major step toward a WWW without digital inequality.


Assuntos
Emprego , Internet , Humanos , Feminino , Paquistão
10.
Trends Biochem Sci ; 46(11): 866-877, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34172362

RESUMO

With sizes <50 kb, viral RNA genomes are at the crossroads of genetic, biophysical, and biochemical stability in their host cell. Here, we analyze the enzymatic assets accompanying large RNA genome viruses, mostly based on recent scientific advances in Coronaviridae. We argue that, in addition to the presence of an RNA exonuclease (ExoN), two markers for the large size of viral RNA genomes are (i) the presence of one or more RNA methyltransferases (MTases) and (ii) a specific architecture of the RNA-dependent RNA polymerase active site. We propose that RNA genome expansion and maintenance are driven by an evolutionary ménage-à-trois made of fast and processive RNA polymerases, RNA repair ExoNs, and RNA MTases that relates to the transition between RNA- to DNA-based life.


Assuntos
Vírus de RNA , Sequência de Aminoácidos , Tamanho do Genoma , Metiltransferases , Vírus de RNA/genética , RNA Viral/genética
11.
J Biol Chem ; 300(6): 107318, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38677513

RESUMO

Sidney Altman's discovery of the processing of one RNA by another RNA that acts like an enzyme was revolutionary in biology and the basis for his sharing the 1989 Nobel Prize in Chemistry with Thomas Cech. These breakthrough findings support the key role of RNA in molecular evolution, where replicating RNAs (and similar chemical derivatives) either with or without peptides functioned in protocells during the early stages of life on Earth, an era referred to as the RNA world. Here, we cover the historical background highlighting the work of Altman and his colleagues and the subsequent efforts of other researchers to understand the biological function of RNase P and its catalytic RNA subunit and to employ it as a tool to downregulate gene expression. We primarily discuss bacterial RNase P-related studies but acknowledge that many groups have significantly contributed to our understanding of archaeal and eukaryotic RNase P, as reviewed in this special issue and elsewhere.


Assuntos
RNA Catalítico , Ribonuclease P , Ribonuclease P/metabolismo , Ribonuclease P/química , Ribonuclease P/genética , História do Século XX , RNA Catalítico/metabolismo , RNA Catalítico/química , RNA Catalítico/genética , História do Século XXI , Humanos
12.
Plant J ; 2024 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-39264984

RESUMO

Lupinus mutabilis is an under-domesticated legume species from the Andean region of South America. It belongs to the New World lupins clade, which groups several lupin species displaying large genetic variation and adaptability to highly different environments. L. mutabilis is attracting interest as a potential multipurpose crop to diversify the European supply of plant proteins, increase agricultural biodiversity, and fulfill bio-based applications. This study reports the first high-quality L. mutabilis genome assembly, which is also the first sequenced assembly of a New World lupin species. Through comparative genomics and phylogenetics, the evolution of L. mutabilis within legumes and lupins is described, highlighting both genomic similarities and patterns specific to L. mutabilis, potentially linked to environmental adaptations. Furthermore, the assembly was used to study the genetics underlying important traits for the establishment of L. mutabilis as a novel crop, including protein and quinolizidine alkaloids contents in seeds, genomic patterns of classic resistance genes, and genomic properties of L. mutabilis mycorrhiza-related genes. These analyses pointed out copy number variation, differential genomic gene contexts, and gene family expansion through tandem duplications as likely important drivers of the genomic diversity observed for these traits between L. mutabilis and other lupins and legumes. Overall, the L. mutabilis genome assembly will be a valuable resource to conduct genetic research and enable genomic-based breeding approaches to turn L. mutabilis into a multipurpose legume crop.

13.
Gastroenterology ; 166(3): 396-408.e2, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37949249

RESUMO

Advances in science have led to the development of multiple biologics and small molecules for the treatment of inflammatory bowel diseases (IBDs). This growth in advanced medical therapies has been accompanied by an increase in methodological innovation to study and compare therapies. Guidelines provide an evidence-based approach to integrating therapies into routine practice, but they are often unable to provide timely recommendations as new therapies come to market, and they have limited incorporation of real-world evidence when making recommendations. This limits the scope and usability of guidelines, and a gap remains in defining how best to position and integrate advanced medical therapies for IBD. In this review, we provide a framework for clinicians and researchers to understand key differences in sources of evidence, how different methodologies are applied to study the comparative effectiveness of advanced medical therapies in IBD, and considerations for how these sources of evidence can be used to better integrate current guideline recommendations. Over time, we anticipate this framework will allow for a transition to living guidelines and/or practice recommendations.


Assuntos
Produtos Biológicos , Doenças Inflamatórias Intestinais , Humanos , Produtos Biológicos/efeitos adversos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Fatores Biológicos
14.
Gastroenterology ; 167(4): 689-703, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38692395

RESUMO

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is a leading cause of cancer death. HCC is preventable with about 70% of HCC attributable to modifiable risk factors. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), Food and Drug Administration-approved medications for treating type 2 diabetes mellitus (T2DM), have pleiotropic effects on counteracting risk factors for HCC. Here we evaluate the association of GLP-1RAs with incident HCC risk in a real-world population. METHODS: This retrospective cohort included 1,890,020 patients with a diagnosis of T2DM who were prescribed GLP-1RAs or other non-GLP-1RA anti-diabetes medications and had no prior diagnosis of HCC. Incident (first-time) diagnosis of HCC and hepatic decompensating events during a 5-year follow-up was compared between cohorts of patients prescribed GLP-1 RAs vs other anti-diabetes medications. Time-to-first-event analysis was performed using Kaplan-Meier survival analysis with hazard ratio and 95% confidence interval calculated. RESULTS: GLP-1RAs were associated with a lower risk of incident HCC with hazard ratio of 0.20 [0.14-0.31], 0.39 [0.21-0.69], 0.63 [0.26-1.50] compared with insulin, sulfonylureas, and metformin, respectively. GLP-1RAs were associated with a significantly lower risk of hepatic decompensation compared with 6 other anti-diabetes medications. Reduced risks were observed in patients without and with different stages of fatty liver diseases, with more profound effects in patients without liver diseases. Similar findings were observed in patients with and without obesity and alcohol or tobacco use disorders. GLP-1RA combination therapies were associated with decreased risk for HCC and hepatic decompensations compared with monotherapies. CONCLUSIONS: GLP-1RAs were associated with a reduced risk of incident HCC and hepatic decompensation compared with other anti-diabetes medications in patients with T2DM. These findings provide supporting evidence for future studies to investigate the underlying mechanisms and their clinical use.


Assuntos
Carcinoma Hepatocelular , Diabetes Mellitus Tipo 2 , Agonistas do Receptor do Peptídeo 1 Semelhante ao Glucagon , Falência Hepática , Neoplasias Hepáticas , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Hepatocelular/epidemiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Agonistas do Receptor do Peptídeo 1 Semelhante ao Glucagon/efeitos adversos , Agonistas do Receptor do Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Incidência , Falência Hepática/epidemiologia , Neoplasias Hepáticas/epidemiologia , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo
15.
RNA ; 29(3): 263-272, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36604112

RESUMO

The modern ribosome catalyzes all coded protein synthesis in extant organisms. It is likely that its core structure is a direct descendant from the ribosome present in the last common ancestor (LCA). Hence, its earliest origins likely predate the LCA and therefore date further back in time. Of special interest is the pseudosymmetrical region (SymR) that lies deep within the large subunit (LSU) where the peptidyl transfer reaction takes place. It was previously proposed that two RNA oligomers, representing the P- and A-regions of extant ribosomes dimerized to create a pore-like structure, which hosted the necessary properties that facilitate peptide bond formation. However, recent experimental studies show that this may not be the case. Instead, several RNA constructs derived exclusively from the P-region were shown to form a homodimer capable of peptide bond synthesis. Of special interest will be the origin issues because the homodimer would have allowed a pre-LCA ribosome that was significantly smaller than previously proposed. For the A-region, the immediate issue will likely be its origin and whether it enhances ribosome performance. Here, we reanalyze the RNA/RNA interaction regions that most likely lead to SymR formation in light of these recent findings. Further, it has been suggested that the ability of these RNA constructs to dimerize and enhance peptide bond formation is sequence-dependent. We have analyzed the implications of sequence variations as parts of functional and nonfunctional constructs.


Assuntos
Evolução Molecular , RNA , RNA/química , Ribossomos/metabolismo , Biossíntese de Proteínas , Peptídeos/genética , Peptídeos/metabolismo
16.
RNA ; 29(8): 1085-1098, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37142437

RESUMO

Darwin's assertion that "it is mere rubbish thinking, at present, of origin of life" is no longer valid. By synthesizing origin of life (OoL) research from its inception to recent findings, with a focus on (i) proof-of-principle prebiotically plausible syntheses and (ii) molecular relics of the ancient RNA World, we present a comprehensive up-to-date description of science's understanding of the OoL and the RNA World hypothesis. Based on these observations, we solidify the consensus that RNA evolved before coded proteins and DNA genomes, such that the biosphere began with an RNA core where much of the translation apparatus and related RNA architecture arose before RNA transcription and DNA replication. This supports the conclusion that the OoL was a gradual process of chemical evolution involving a series of transitional forms between prebiotic chemistry and the last universal common ancestor (LUCA) during which RNA played a central role, and that many of the events and their relative order of occurrence along this pathway are known. The integrative nature of this synthesis also extends previous descriptions and concepts and should help inform future questions and experiments about the ancient RNA World and the OoL.


Assuntos
Replicação do DNA , RNA , RNA/genética , RNA/química , DNA , Evolução Molecular , Origem da Vida
17.
J Pathol ; 262(3): 255-270, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38180354

RESUMO

The fifth edition of the World Health Organization Classification of Haematolymphoid Tumours (WHO-HAEM5) is the product of an evidence-based evolution of the revised fourth edition with wide multidisciplinary consultation. Nonetheless, while every classification incorporates scientific advances and aims to improve upon the prior version, medical knowledge remains incomplete and individual neoplasms may not be easily subclassified in a given scheme. Thus, optimal classification requires ongoing study, and there are certain aspects of some entities and subtypes that require further refinements. In this review, we highlight a selection of these challenging areas to prompt more research investigations. These include (1) a 'placeholder term' of splenic B-cell lymphoma/leukaemia with prominent nucleoli (SBLPN) to accommodate many of the splenic lymphomas previously classified as hairy cell leukaemia variant and B-prolymphocytic leukaemia, a clear new start to define their pathobiology; (2) how best to classify BCL2 rearrangement negative follicular lymphoma including those with BCL6 rearrangement, integrating the emerging new knowledge on various germinal centre B-cell subsets; (3) what is the spectrum of non-IG gene partners of MYC translocation in diffuse large B-cell lymphoma/high-grade B-cell lymphoma and how they impact MYC expression and clinical outcome; how best to investigate this in a routine clinical setting; and (4) how best to define high-grade B-cell lymphoma not otherwise specified and high-grade B-cell lymphoma with 11q aberrations to distinguish them from their mimics and characterise their molecular pathogenetic mechanism. Addressing these questions would provide more robust evidence to better define these entities/subtypes, improve their diagnosis and/or prognostic stratification, leading to better patient care. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.


Assuntos
Linfoma Difuso de Grandes Células B , Humanos , Linfoma Difuso de Grandes Células B/classificação , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2/genética , Translocação Genética , Reino Unido , Organização Mundial da Saúde
20.
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