-
The Plant Cell Jan 2023Maize (Zea mays) originated in southern Mexico and has spread over a wide latitudinal range. Maize expansion from tropical to temperate regions has necessitated a...
Maize (Zea mays) originated in southern Mexico and has spread over a wide latitudinal range. Maize expansion from tropical to temperate regions has necessitated a reduction of its photoperiod sensitivity. In this study, we cloned a quantitative trait locus (QTL) regulating flowering time in maize and show that the maize ortholog of Arabidopsis thaliana EARLY FLOWERING3, ZmELF3.1, is the causal locus. We demonstrate that ZmELF3.1 and ZmELF3.2 proteins can physically interact with ZmELF4.1/4.2 and ZmLUX1/2, to form evening complex(es; ECs) in the maize circadian clock. Loss-of-function mutants for ZmELF3.1/3.2 and ZmLUX1/2 exhibited delayed flowering under long-day and short-day conditions. We show that EC directly represses the expression of several flowering suppressor genes, such as the CONSTANS, CONSTANS-LIKE, TOC1 (CCT) genes ZmCCT9 and ZmCCT10, ZmCONSTANS-LIKE 3, and the PSEUDORESPONSE REGULATOR (PRR) genes ZmPRR37a and ZmPRR73, thus alleviating their inhibition, allowing florigen gene expression and promoting flowering. Further, we identify two closely linked retrotransposons located in the ZmELF3.1 promoter that regulate the expression levels of ZmELF3.1 and may have been positively selected during postdomestication spread of maize from tropical to temperate regions during the pre-Columbian era. These findings provide insights into circadian clock-mediated regulation of photoperiodic flowering in maize and new targets of genetic improvement for breeding.
Topics: Zea mays; Flowers; Plant Proteins; Adaptation, Physiological; Acclimatization; Photoperiod; Arabidopsis; Gene Expression Regulation, Plant
PubMed: 36173348
DOI: 10.1093/plcell/koac296 -
The Plant Cell Oct 2020Circadian clocks regulate growth and development in plants and animals, but the role of circadian regulation in crop production is poorly understood. Rice () grain yield...
Circadian clocks regulate growth and development in plants and animals, but the role of circadian regulation in crop production is poorly understood. Rice () grain yield is largely determined by tillering, which is mediated by physiological and genetic factors. Here we report a regulatory loop that involves the circadian clock, sugar, and strigolactone (SL) pathway to regulate rice tiller-bud and panicle development. Rice () positively regulates expression of (, also known as ), (), and (, also known as ) to repress tiller-bud outgrowth. Downregulating and overexpressing increases and reduces tiller numbers, respectively, whereas manipulating () expression results in the opposite effects. also regulates expression to mediate panicle and grain development. Genetic analyses using double mutants and overexpression in the mutants show that , , and act downstream of Sugars repress expression in roots and tiller buds to promote tiller-bud outgrowth. The circadian clock integrates sugar responses and the SL pathway to regulate tiller and panicle development, providing insights into improving plant architecture and yield in rice and other cereal crops.
Topics: Circadian Clocks; Gene Expression Regulation, Plant; Heterocyclic Compounds, 3-Ring; Lactones; Mutation; Oryza; Plant Proteins; Plants, Genetically Modified; Promoter Regions, Genetic; Signal Transduction; Sugars
PubMed: 32796126
DOI: 10.1105/tpc.20.00289 -
The EMBO Journal Feb 2021The roles of clock components in salt stress tolerance remain incompletely characterized in rice. Here, we show that, among OsPRR (Oryza sativa Pseudo-Response...
The roles of clock components in salt stress tolerance remain incompletely characterized in rice. Here, we show that, among OsPRR (Oryza sativa Pseudo-Response Regulator) family members, OsPRR73 specifically confers salt tolerance in rice. Notably, the grain size and yield of osprr73 null mutants were significantly decreased in the presence of salt stress, with accumulated higher level of reactive oxygen species and sodium ions. RNA sequencing and biochemical assays identified OsHKT2;1, encoding a plasma membrane-localized Na transporter, as a transcriptional target of OsPRR73 in mediating salt tolerance. Correspondingly, null mutants of OsHKT2;1 displayed an increased tolerance to salt stress. Immunoprecipitation-mass spectrometry (IP-MS) assays further identified HDAC10 as nuclear interactor of OsPRR73 and co-repressor of OsHKT2;1. Consistently, H3K9ac histone marks at OsHKT2;1 promoter regions were significantly reduced in osprr73 mutant. Together, our findings reveal that salt-induced OsPRR73 expression confers salt tolerance by recruiting HDAC10 to transcriptionally repress OsHKT2;1, thus reducing cellular Na accumulation. This exemplifies a new molecular link between clock components and salt stress tolerance in rice.
Topics: CLOCK Proteins; Cell Membrane; Gene Expression Regulation, Plant; Histone Deacetylases; Homeostasis; Loss of Function Mutation; Oryza; Plant Proteins; Promoter Regions, Genetic; Salt Tolerance; Sodium
PubMed: 33347628
DOI: 10.15252/embj.2020105086 -
Neuro-oncology Advances 2022Glioblastoma (GBM) is the most common primary adult intracranial malignancy and carries a dismal prognosis despite an aggressive multimodal treatment regimen that... (Review)
Review
Glioblastoma (GBM) is the most common primary adult intracranial malignancy and carries a dismal prognosis despite an aggressive multimodal treatment regimen that consists of surgical resection, radiation, and adjuvant chemotherapy. Radiographic evaluation, largely informed by magnetic resonance imaging (MRI), is a critical component of initial diagnosis, surgical planning, and post-treatment monitoring. However, conventional MRI does not provide information regarding tumor microvasculature, necrosis, or neoangiogenesis. In addition, traditional MRI imaging can be further confounded by treatment-related effects such as pseudoprogression, radiation necrosis, and/or pseudoresponse(s) that preclude clinicians from making fully informed decisions when structuring a therapeutic approach. A myriad of novel imaging modalities have been developed to address these deficits. Herein, we provide a clinically oriented review of standard techniques for imaging GBM and highlight emerging technologies utilized in disease characterization and therapeutic development.
PubMed: 35821676
DOI: 10.1093/noajnl/vdac080 -
BJR Open 2020Inaccurate assessment of surveillance imaging to assess response to glioma therapy may have life-changing consequences. Varied management plans including chemotherapy,... (Review)
Review
Inaccurate assessment of surveillance imaging to assess response to glioma therapy may have life-changing consequences. Varied management plans including chemotherapy, radiotherapy or immunotherapy may all contribute to heterogeneous post-treatment appearances and the overlap between the morphological features of pseudoprogression, pseudoresponse and radiation necrosis can make their discrimination very challenging. Therefore, there has been a drive to develop objective strategies for post-treatment assessment of brain gliomas. This review discusses the most important of these approaches such as the RANO "Response Assessment in Neuro-Oncology", iRANO "Immunotherapy Response Assessment in Neuro-Oncology" and RAPNO "Response Assessment in Paediatric Neuro-Oncology" models. In addition to these systematic approaches for glioma surveillance, the relatively limited information provided by conventional imaging modalities alone has motivated the development of novel advanced magnetic resonance (MR) and metabolic imaging methods for further discrimination between viable tumour and treatment induced changes. Multiple clinical trials and meta-analyses have investigated the diagnostic performance of these novel techniques in the follow up of brain gliomas, including both single modality descriptive studies and comparative imaging assessment. In this manuscript, we review the literature and discuss the promises and pitfalls of frequently studied modalities in glioma surveillance imaging, including MR perfusion, MR diffusion and MR spectroscopy. In addition, we evaluate other promising MR techniques such as chemical exchange saturation transfer as well as fludeoxyglucose and non-FDG positron emission tomography techniques.
PubMed: 33178973
DOI: 10.1259/bjro.20200009 -
Neuro-oncology Aug 2022Diffuse Midline Glioma (DMG) with the H3K27M mutation is a lethal childhood brain cancer, with patients rarely surviving 2 years from diagnosis.
BACKGROUND
Diffuse Midline Glioma (DMG) with the H3K27M mutation is a lethal childhood brain cancer, with patients rarely surviving 2 years from diagnosis.
METHODS
We conducted a multi-site Phase 1 trial of the imipridone ONC201 for children with H3K27M-mutant glioma (NCT03416530). Patients enrolled on Arm D of the trial (n = 24) underwent serial lumbar puncture for cell-free tumor DNA (cf-tDNA) analysis and patients on all arms at the University of Michigan underwent serial plasma collection. We performed digital droplet polymerase chain reaction (ddPCR) analysis of cf-tDNA samples and compared variant allele fraction (VAF) to radiographic change (maximal 2D tumor area on MRI).
RESULTS
Change in H3.3K27M VAF over time ("VAF delta") correlated with prolonged PFS in both CSF and plasma samples. Nonrecurrent patients that had a decrease in CSF VAF displayed a longer progression free survival (P = .0042). Decrease in plasma VAF displayed a similar trend (P = .085). VAF "spikes" (increase of at least 25%) preceded tumor progression in 8/16 cases (50%) in plasma and 5/11 cases (45.4%) in CSF. In individual cases, early reduction in H3K27M VAF predicted long-term clinical response (>1 year) to ONC201, and did not increase in cases of later-defined pseudo-progression.
CONCLUSION
Our work demonstrates the feasibility and potential utility of serial cf-tDNA in both plasma and CSF of DMG patients to supplement radiographic monitoring. Patterns of change in H3K27M VAF over time demonstrate clinical utility in terms of predicting progression and sustained response and possible differentiation of pseudo-progression and pseudo-response.
Topics: Brain Neoplasms; Child; Circulating Tumor DNA; Glioma; Histones; Humans; Imidazoles; Mutation; Pyridines; Pyrimidines
PubMed: 35137228
DOI: 10.1093/neuonc/noac030 -
Diagnostics (Basel, Switzerland) Mar 2022In this comprehensive review we present an update on the most relevant studies evaluating the utility of amino acid PET radiotracers for the evaluation of glioma... (Review)
Review
AIM
In this comprehensive review we present an update on the most relevant studies evaluating the utility of amino acid PET radiotracers for the evaluation of glioma recurrence as compared to magnetic resonance imaging (MRI).
METHODS
A literature search extended until June 2020 on the PubMed/MEDLINE literature database was conducted using the terms "high-grade glioma", "glioblastoma", "brain tumors", "positron emission tomography", "PET", "amino acid PET", "[C]methyl-l-methionine", "[F]fluoroethyl-tyrosine", "[F]fluoro-l-dihydroxy-phenylalanine", "MET", "FET", "DOPA", "magnetic resonance imaging", "MRI", "advanced MRI", "magnetic resonance spectroscopy", "perfusion-weighted imaging", "diffusion-weighted imaging", "MRS", "PWI", "DWI", "hybrid PET/MR", "glioma recurrence", "pseudoprogression", "PSP", "treatment-related change", and "radiation necrosis" alone and in combination. Only original articles edited in English and about humans with at least 10 patients were included.
RESULTS
Forty-four articles were finally selected. Conventional amino acid PET tracers were demonstrated to be reliable diagnostic techniques in differentiating tumor recurrence thanks to their high uptake from tumor tissue and low background in normal grey matter, giving additional and early information to standard modalities. Among them, MET-PET seems to present the highest diagnostic value but its use is limited to on-site cyclotron facilities. [F]labelled amino acids, such as FDOPA and FET, were developed to provide a more suitable PET tracer for routine clinical applications, and demonstrated similar diagnostic performance. When compared to the gold standard MRI, amino acid PET provides complementary and comparable information to standard modalities and seems to represent an essential tool in the differentiation between tumor recurrence and other entities such as pseudoprogression, radiation necrosis, and pseudoresponse.
CONCLUSIONS
Despite the introduction of new advanced imaging techniques, the diagnosis of glioma recurrence remains challenging. In this scenario, the growing knowledge about imaging techniques and analysis, such as the combined PET/MRI and the application of artificial intelligence (AI) and machine learning (ML), could represent promising tools to face this difficult and debated clinical issue.
PubMed: 35453892
DOI: 10.3390/diagnostics12040844 -
Current Oncology Reports Feb 2021This review will explore the latest in advanced imaging techniques, with a focus on the complementary nature of multiparametric, multimodality imaging using magnetic... (Review)
Review
PURPOSE OF REVIEW
This review will explore the latest in advanced imaging techniques, with a focus on the complementary nature of multiparametric, multimodality imaging using magnetic resonance imaging (MRI) and positron emission tomography (PET).
RECENT FINDINGS
Advanced MRI techniques including perfusion-weighted imaging (PWI), MR spectroscopy (MRS), diffusion-weighted imaging (DWI), and MR chemical exchange saturation transfer (CEST) offer significant advantages over conventional MR imaging when evaluating tumor extent, predicting grade, and assessing treatment response. PET performed in addition to advanced MRI provides complementary information regarding tumor metabolic properties, particularly when performed simultaneously. F-fluoroethyltyrosine (FET) PET improves the specificity of tumor diagnosis and evaluation of post-treatment changes. Incorporation of radiogenomics and machine learning methods further improve advanced imaging. The complementary nature of combining advanced imaging techniques across modalities for brain tumor imaging and incorporating technologies such as radiogenomics has the potential to reshape the landscape in neuro-oncology.
Topics: Brain Neoplasms; Diffusion Magnetic Resonance Imaging; Humans; Magnetic Resonance Imaging; Positron-Emission Tomography
PubMed: 33599882
DOI: 10.1007/s11912-021-01020-2 -
Cancers Mar 2022Gliomas, and glioblastoma in particular, exhibit an extensive intra- and inter-tumoral molecular heterogeneity which represents complex biological features correlating... (Review)
Review
Gliomas, and glioblastoma in particular, exhibit an extensive intra- and inter-tumoral molecular heterogeneity which represents complex biological features correlating to the efficacy of treatment response and survival. From a neuroimaging point of view, these specific molecular and histopathological features may be used to yield imaging biomarkers as surrogates for distinct tumor genotypes and phenotypes. The development of comprehensive glioma imaging markers has potential for improved glioma characterization that would assist in the clinical work-up of preoperative treatment planning and treatment effect monitoring. In particular, the differentiation of tumor recurrence or true progression from pseudoprogression, pseudoresponse, and radiation-induced necrosis can still not reliably be made through standard neuroimaging only. Given the abundant vascular and hemodynamic alterations present in diffuse glioma, advanced hemodynamic imaging approaches constitute an attractive area of clinical imaging development. In this context, the inclusion of objective measurable glioma imaging features may have the potential to enhance the individualized care of diffuse glioma patients, better informing of standard-of-care treatment efficacy and of novel therapies, such as the immunotherapies that are currently increasingly investigated. In Part B of this two-review series, we assess the available evidence pertaining to hemodynamic imaging for molecular feature prediction, in particular focusing on isocitrate dehydrogenase (IDH) mutation status, MGMT promoter methylation, 1p19q codeletion, and EGFR alterations. The results for the differentiation of tumor progression/recurrence from treatment effects have also been the focus of active research and are presented together with the prognostic correlations identified by advanced hemodynamic imaging studies. Finally, the state-of-the-art concepts and advancements of hemodynamic imaging modalities are reviewed together with the advantages derived from the implementation of radiomics and machine learning analyses pipelines.
PubMed: 35267650
DOI: 10.3390/cancers14051342 -
Frontiers in Oncology 2023Progressive enhancement predicted poor survival in ACRIN 6677/RTOG 0625, a multi-center trial of bevacizumab with irinotecan or temozolomide in recurrent glioblastoma,...
BACKGROUND
Progressive enhancement predicted poor survival in ACRIN 6677/RTOG 0625, a multi-center trial of bevacizumab with irinotecan or temozolomide in recurrent glioblastoma, but pseudoresponse likely limited enhancement-based survival prognostication in T1 non-progressors. We aimed to determine whether early change in cerebral blood volume from baseline (ΔCBV) could further stratify the T1 non-progressors according to overall (OS) and progression-free (PFS) survival.
METHODS
37/123 enrolled patients had DSC-MRI, including 13, 15, and 8 patients without 2D-T1 progression at 2, 8, and 16 weeks post-treatment initiation, respectively. Mean CBV normalized to white matter (nRCBV) and mean standardized CBV (sRCBV) were extracted from enhancing tumor. ROC curves were derived for ΔCBV using six-month PFS and one-year OS as reference standards. Kaplan-Meier survival estimates and log-rank test compared PFS and OS for both ΔCBV (increase vs. decrease) and T1 response status (stable vs. decreasing enhancement).
RESULTS
PFS and OS were significantly worse for increasing CBV at 2 weeks (p=0.003 and p=0.002 for nRCBV, and p=0.03 and p=0.03 for sRCBV, respectively), but not for 2D-T1 patients with stable vs. decreasing enhancement (p=0.44 and p=0.86, respectively). ΔCBV at week 2 was also a good prognostic marker for OS-1 and PFS-6 using ROC analysis. By contrast, 2D-T1 response status at weeks 2, 8, and 16 was not associated with PFS-6. ΔCBV at 16 weeks (p=0.008 for sRCBV) but not 8 weeks (p=0.74 for nRCBV and p=0.56 for sRCBV) was associated with significant difference in median survival, but no difference in survival was observed for 2D-T1 patients with stable vs. decreasing enhancement at 8 weeks (p=0.69) or 16 weeks (p=0.21). At 16 weeks, OS did not differ significantly between 2D-T1 progressors and 2D-T1 non-progressors with increasing CBV (median survival 3.3 months post week 16 scan vs. 9.2 months, respectively; p=0.13), suggesting that 2D-T1 non-progressors with increasing CBV may have a prognosis like that of 2D-T1 progressors.
CONCLUSION
After 2 weeks of anti-angiogenic therapy, ΔCBV in 2D-T1 non-progressors significantly prognosticated PFS and OS, whereas 2D-T1 response status did not, identifying a subpopulation that benefits from bevacizumab. Combining 2D-T1 progression and ΔCBV may yield a response assessment paradigm with 3-tiered OS stratification.
PubMed: 36776298
DOI: 10.3389/fonc.2023.1061502