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39057576_p2
|
39057576
|
sec[0]/sec[0]/p[1]
|
1.1. Pathophysiology of Motor Deficit after Stroke
| 3.972656 |
biomedical
|
Review
|
[
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[
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In haemorrhagic stroke, bleeding in the affected brain region results in the compression of neuronal tissue via haematoma formation and increased intracranial pressure, followed by secondary inflammation and oedema, blood–brain barrier disruption and hypoperfusion in the region adjacent to the haematoma . Haemorrhagic stroke generally results in more severe initial upper limb motor impairment; however, patients with this type of stroke experience a more rapid recovery of symptoms, suggesting that the long-term outcomes are similar for both types of strokes .
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
39057576_p3
|
39057576
|
sec[0]/sec[1]/p[0]
|
1.2. Upper Limb Impairment after Stroke
| 4.035156 |
biomedical
|
Study
|
[
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0.0001659393310546875
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[
0.90625,
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Upper limb impairment occurs in approximately 50–80% of acute stroke survivors and is still present in around 50% of patients 6 months later during the chronic phase . In contrast, up to 85% of survivors can walk independently within 6 months . Upper limb impairments include incoordination, paresis or paralysis; reduced somatosensation, range of movement, speed or dexterity; and hypertonia ( Table 1 ) . Additionally, other neurological consequences such as apraxia may impede upper limb function, where the stroke survivor is unable to execute previously learned motor skills or tasks .
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057576_p4
|
39057576
|
sec[0]/sec[1]/p[1]
|
1.2. Upper Limb Impairment after Stroke
| 3.302734 |
biomedical
|
Other
|
[
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0.0025272369384765625
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[
0.022674560546875,
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] |
Persistent upper limb motor deficit is associated with more severe disability and reduced independence. As such, it needs to be promptly addressed to enable patients to continue to perform their activities of daily living (ADLs) such as washing, dressing, cooking, eating and using the toilet . Reduced motor ability puts stroke survivors at risk of having to reduce their working hours or retire from employment altogether . It is reported that only half of all stroke survivors retain the same working pattern one year after their stroke .
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057576_p5
|
39057576
|
sec[0]/sec[2]/p[0]
|
1.3. Upper Limb Impairment and Quality of Life
| 3.957031 |
biomedical
|
Review
|
[
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0.0010137557983398438
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[
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Upper limb impairment after stroke extends far beyond functional deficits alone; it is well documented that a patient’s quality of life (QoL) can be heavily impacted by stroke . Patients are less able to sustain previous family roles such as working or caring for their children or parents. Stroke survivors are more likely to depend on their families for support, and experience reduced satisfaction in relationships with their partners . Physical disabilities also adversely affect their career aspirations, social life or hobbies and drastically shift the dynamic onto a situation centred around completing basic ADLs . Figure 1 demonstrates the issues resulting from upper limb impairment after stroke according to the International Classification of Functioning, Disability and Health (ICF) model .
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057576_p6
|
39057576
|
sec[0]/sec[3]/p[0]
|
1.4. Management Approaches for Upper Limb Impairment
| 3.4375 |
biomedical
|
Other
|
[
0.88232421875,
0.1103515625,
0.00708770751953125
] |
[
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] |
Currently, in the UK and a large proportion of Europe, stroke patients are treated in specialised stroke units with a dedicated multidisciplinary team (MDT) promoting rehabilitation . For patients with altered sensation, motor deficits, reduced coordination or impairment of the upper limbs, physiotherapy and occupational therapy are offered to address impaired structure and function, activity limitation and restricted participation. Alongside this, many other specific interventions are considered depending on patient circumstances.
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057576_p7
|
39057576
|
sec[0]/sec[4]/p[0]
|
1.5. Stroke Rehabilitation Guidelines
| 2.347656 |
clinical
|
Other
|
[
0.416748046875,
0.56005859375,
0.0230560302734375
] |
[
0.0020904541015625,
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0.006938934326171875
] |
Clinical guidelines are needed to inform clinical practise, tailor interventions to improve patients’ outcomes, direct rehabilitation service commissioners to invest in evidence-based interventions and address unresolved research questions .
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057576_p8
|
39057576
|
sec[0]/sec[4]/p[1]
|
1.5. Stroke Rehabilitation Guidelines
| 2.304688 |
biomedical
|
Other
|
[
0.91162109375,
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0.0340576171875
] |
[
0.0012073516845703125,
0.96875,
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0.0019292831420898438
] |
In the UK, the national guidelines on stroke management and rehabilitation are produced by two major organisations, namely the National Institute for Health and Care Excellence (NICE) and the Intercollegiate Stroke Working Party (ISWP) . Acute stroke management and rehabilitation guidelines were originally published by the NICE and ISWP in 2013 and 2016, respectively. Both guidelines were updated in 2023 to incorporate new evidence in rehabilitation interventions, including those relating to upper limb motor recovery .
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057576_p9
|
39057576
|
sec[0]/sec[4]/p[2]
|
1.5. Stroke Rehabilitation Guidelines
| 3.75 |
biomedical
|
Other
|
[
0.76123046875,
0.181396484375,
0.0574951171875
] |
[
0.00243377685546875,
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0.004314422607421875
] |
Guidelines produced by the NICE help healthcare practitioners and commissioners to provide high-quality care that is cost-effective. These guidelines are based on rigorous and independent analysis of complex evidence, developing recommendations on key areas and promoting the uptake of best practises and policies to improve clinical outcomes. The NICE produces several evidence-based clinical guidelines on many conditions, including stroke . The NICE Guidelines are developed following a rigorous methodological approach. Initially, a draft scope is created, and a guideline committee is recruited. A consultation on the draft scope is held, and a final scope is then released. The published evidence is then searched and summarised. Committee members review the evidence, including health economic evidence, and agree on a draft guideline. Subsequently, a consultation exercise is undertaken with relevant stakeholders seeking feedback which informs revisions. The guideline is then published. Guidelines are updated on a regular basis according to the latest available evidence . The NICE stroke rehabilitation guidelines use specific terms in their recommendations, such as ‘consider’, ‘offer’, ‘do not offer’ and ‘do not routinely offer’. The strength of recommendation used depends on the level of evidence for specific interventions .
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057576_p10
|
39057576
|
sec[0]/sec[4]/p[3]
|
1.5. Stroke Rehabilitation Guidelines
| 3.181641 |
biomedical
|
Other
|
[
0.73291015625,
0.19775390625,
0.06915283203125
] |
[
0.0023174285888671875,
0.9921875,
0.004184722900390625,
0.0012178421020507812
] |
The ISWP, set up by the Royal College of Physicians (RCP), is dedicated to producing evidence-based stroke guidelines to improve the quality of care delivered to all adult stroke survivors in the UK and Ireland. Its committee consists of a group of senior representatives from professional bodies in England, Wales and Northern Ireland involved in stroke care (such as occupational therapists, physiotherapists and speech and language therapists), in addition to representatives from the voluntary sector and patient and carer representatives. The ISWP guidance is produced by a development group including members from the Scottish Intercollegiate Guidelines Network (SIGN) and the Irish National Clinical Programme for Stroke. The group is supported by a project team from the Sentinel Stroke National Audit Programme at King’s College London. The ISWP used a standardised seven-step methodology to develop their guidelines, including developing a scope, performing a literature search, selecting the included studies, evidence analysis, drafting recommendations, considering health economic implications, external peer review and public consultation of drafted guidelines. In the guidelines, the ISWP uses terms such as ‘should be’, (offered, considered) ‘may be’, (considered) ‘should not be’ (treated, used) and ‘should not be routinely offered’ .
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057576_p11
|
39057576
|
sec[0]/sec[4]/p[4]
|
1.5. Stroke Rehabilitation Guidelines
| 3.802734 |
biomedical
|
Other
|
[
0.9140625,
0.0823974609375,
0.0035228729248046875
] |
[
0.086181640625,
0.603515625,
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0.0160064697265625
] |
The European Stroke Organisation (ESO), a pan-European society focussing on stroke-related research, also published a clinical guideline on stroke rehabilitation in 2023, including motor recovery of the upper limbs. These recommendations are based on high-quality clinical guidelines published between 2016 and 2022 from the UK, Australia/New Zealand, Canada, the United States of America and the Netherlands. An expert European working group searched the literature for national clinical practise. Stroke guidelines written in English or Dutch with a section on rehabilitation after stroke were included. Two researchers then independently reviewed the guidelines and collated interventions which were recommended by at least three of the guidelines. Since the recommendations were based on support from at least three guidelines, they had high levels of evidence and were, therefore, all ‘strongly recommended’ .
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057576_p12
|
39057576
|
sec[0]/sec[5]/p[0]
|
1.6. Aims and Objectives
| 4.078125 |
biomedical
|
Review
|
[
0.970703125,
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] |
[
0.00341796875,
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] |
The objective of this review was to provide a summary document of the NICE, ISWP and ESO 2023 guidelines relating to upper limb motor recovery. Our aim was to collate recommendations from all three guidelines in one review to support a future consensus statement for UK and European stroke service providers and patients. A comprehensive understanding of which interventions are recommended, at what dose, when, who delivers them and in which setting is critical to improving patients’ outcomes. The ESO 2023 guidelines were included because they complement the UK guidelines and provide a comprehensive summary of several other guidelines from Australia, New Zealand, Canada, the Netherlands and the US published between 2016 and 2022. It is worth noting that the only UK guideline referenced by the ESO in 2023 was the ISWP guidance published in 2016 . NICE guidelines were not included as they dated back to 2013 . Since 2016, both ISWP and NICE updated their clinical guidelines on stroke rehabilitation with new recommendations based on updated research evidence .
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057576_p13
|
39057576
|
sec[0]/sec[5]/p[1]
|
1.6. Aims and Objectives
| 1.762695 |
biomedical
|
Review
|
[
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0.027618408203125,
0.14208984375
] |
[
0.00534820556640625,
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] |
While stroke guidelines were also published previously by SIGN in 2010, they were not included in this review, because the guidelines were based on evidence which has since been updated . Additionally, the SIGN guidelines have been superseded by the National Clinical Guideline for Stroke , which SIGN collaborated with ISWP and other bodies to produce . Similarly, other relevant guidelines such as from the US American Heart Association/American Stroke Association were not included as they were out of date due to being published in 2016. However, they were featured in the ESO 2023 guidelines to inform their recommendations .
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057576_p14
|
39057576
|
sec[1]/p[0]
|
2. Materials and Methods
| 4.066406 |
biomedical
|
Review
|
[
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[
0.128662109375,
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0.86865234375,
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] |
The stroke rehabilitation guidelines from the UK, namely NICE and ISWP published in 2023, and the 2023 ESO guidelines were retrieved. The two reviewers individually identified sections where the terms motor, recovery, upper limb, rehabilitation, interventions, approaches or technology in relation to the upper limb were used. After discussion, both authors agreed on specific categories to be included in this review. Both authors then agreed to collate the recommendations into 3 sections and tables: general rehabilitation approaches, technology- and device-assisted rehabilitation, and spasticity management ( Table 2 , Table 3 and Table 4 ) . The relevant sections on upper limb motor recovery were then analysed by the two authors independently to identify similarities and differences. Agreement between guidelines was noted if the guidelines used the terms ‘recommend’, ‘strongly recommend’ or ‘offer’. A difference between guidelines was observed when they used different terms such as ‘consider’ when the other guideline used ‘offer’ or ‘strongly recommend’. Where there was a difference in opinion between the two authors, this difference was resolved by an in-depth discussion. The result tables were then populated and revised, and a consensus was reached. The authors followed the same approach used by the ESO to inform our methodology .
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057576_p15
|
39057576
|
sec[2]/sec[0]/p[0]
|
3.1. Upper Limb Stroke Guidelines
| 3.847656 |
biomedical
|
Review
|
[
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] |
[
0.031280517578125,
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0.9462890625,
0.0008511543273925781
] |
In this section, the two authors summarise the UK (NICE and ISWP) and ESO guidelines relating to upper limb motor recovery after stroke in Table 2 , Table 3 and Table 4 . Table 2 describes the general approaches to upper limb rehabilitation after stroke, while Table 3 summarises the technology- and device-assisted rehabilitation method guidelines. Similarly, Table 4 details a summary of spasticity management in the context of upper limb motor recovery ( Table 2 , Table 3 and Table 4 ) .
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057576_p16
|
39057576
|
sec[2]/sec[1]/sec[0]/p[0]
|
3.2.1. Therapeutic Intensity
| 2.792969 |
biomedical
|
Other
|
[
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[
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0.0037517547607421875
] |
The ISWP and NICE recommendations are the same for intensity as they both advise a minimum of three hours of therapy on at least five days per week. Personalised rehabilitation types and intensity are also recommended by NICE and ISWP, which should be offered by a range of multidisciplinary team members . Similarly, the ESO strongly recommends that rehabilitation is structured to provide as much therapy (occupational and physiotherapy) as possible . However, it does not include a specific minimum or maximum target of therapy duration or frequency to aim for in the context of upper extremity rehabilitation .
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057576_p17
|
39057576
|
sec[2]/sec[1]/sec[1]/p[0]
|
3.2.2. Strength Training
| 2.464844 |
biomedical
|
Other
|
[
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[
0.0018978118896484375,
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The ISWP recommends and the ESO strongly recommends offering strength training to stroke patients, while the NICE states that strength training should be considered. All three guidelines provide differing details on specific approaches to strength training. While the ESO strongly recommends resistance training as a form of strength training, the NICE also mentions resistance training as well as bodyweight activities and weights as two other forms. Similarly, the ISWP recommends two forms of strength training: bodyweight activities and mixed training, which includes resistance training .
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
39057576_p18
|
39057576
|
sec[2]/sec[1]/sec[2]/p[0]
|
3.2.3. Task-Specific Training/Repetitive Task Training
| 3.931641 |
biomedical
|
Review
|
[
0.96044921875,
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] |
[
0.01201629638671875,
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Agreement was found between all three guidelines for this approach. The NICE and ISWP recommend, while the ESO strongly recommends, offering task-specific training (TST)/repetitive task training (RTT) . In terms of RTT, the ISWP recommends that RTT should be the principal rehabilitation method alongside traditional exercise and advises healthcare providers that a unilateral or bilateral upper limb approach could be taken when offering RTT, depending on the task and level of impairment. Moreover, the ISWP uniquely clarifies that cognitive impairment should not prevent patients from being offered RTT and suggests it can be enhanced with trunk restraint or priming techniques . While the ISWP specifies RTT should be intensive, task-specific, functional and consisting of a high number of repetitions, the ESO advises RTT should be intensive, task-specific, progressively adaptive, goal-oriented and meaningful . Finally, the NICE offers multiple examples of RTT to consider, such as reaching or grasping .
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057576_p19
|
39057576
|
sec[2]/sec[1]/sec[3]/p[0]
|
3.2.4. Mental Practice
| 1.982422 |
biomedical
|
Other
|
[
0.8232421875,
0.0751953125,
0.10150146484375
] |
[
0.0015897750854492188,
0.9921875,
0.00484466552734375,
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] |
The ISWP recommends, and the ESO strongly recommends, mental practise (MP) as an adjunct to conventional upper extremity motor rehabilitation therapies . The ISWP additionally specifies that mental practise should be offered to individuals who are both motivated and able to participate .
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057576_p20
|
39057576
|
sec[2]/sec[2]/sec[0]/p[0]
|
3.3.1. Constraint-Induced Movement Therapy
| 2.703125 |
biomedical
|
Other
|
[
0.92822265625,
0.044891357421875,
0.02679443359375
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[
0.0037841796875,
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Agreement exists between the NICE and ISWP guidelines, which both recommend considering constraint-induced movement therapy (CIMT) use. The ESO guidelines differ as they strongly recommend offering traditional or modified CIMT. However, the ESO does not advise on any qualifying criteria for CIMT in terms of range of movement . The NICE specifically highlights awareness of the potentially adverse effects associated with CIMT, such as low mood .
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057576_p21
|
39057576
|
sec[2]/sec[2]/sec[1]/p[0]
|
3.3.2. Splinting/Orthoses
| 1.799805 |
biomedical
|
Other
|
[
0.63818359375,
0.3310546875,
0.0308990478515625
] |
[
0.0028171539306640625,
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] |
Both the NICE and ISWP also recommend that splints are fitted and monitored by appropriately trained staff .
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057576_p22
|
39057576
|
sec[2]/sec[2]/sec[2]/p[0]
|
3.3.3. Electrical Stimulation
| 3.509766 |
biomedical
|
Other
|
[
0.71875,
0.2587890625,
0.022430419921875
] |
[
0.0030994415283203125,
0.8349609375,
0.15576171875,
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] |
The NICE advises that electrical stimulation (ES) should continually be offered if there is evidence of functional progression demonstrated, with the ISWP similarly stating that stimulation protocols should be tailored to the individual. Meanwhile, the ISWP limits consideration of ES to wrist and finger extensors limiting function as the desired criteria. The ISWP additionally states that training related to ES should be offered to the patient, their family or carers and involved healthcare professionals . In terms of specific forms of ES, the ESO only recommends NMES, while the ISWP specifically recommends FES and the NICE guidelines do not specify a form of ES to be offered .
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057576_p23
|
39057576
|
sec[2]/sec[2]/sec[3]/p[0]
|
3.3.4. Vagus Nerve Stimulation
| 2.285156 |
biomedical
|
Other
|
[
0.9619140625,
0.0307769775390625,
0.007358551025390625
] |
[
0.0045013427734375,
0.970703125,
0.021881103515625,
0.00289154052734375
] |
Only the ISWP guidelines include VNS, whereby they specify that transcutaneous VNS could be considered for mild-to-moderate arm weakness. Furthermore, they highlight that implanted VNS could be considered in the context of clinical trials .
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
39057576_p24
|
39057576
|
sec[2]/sec[2]/sec[4]/p[0]
|
3.3.5. Mirror Therapy
| 1.806641 |
biomedical
|
Other
|
[
0.72705078125,
0.2109375,
0.06195068359375
] |
[
0.0018262863159179688,
0.9912109375,
0.00415802001953125,
0.0026035308837890625
] |
The NICE states that mirror therapy should be started within the first 6 months following a stroke, and describe the ideal length, frequency and level of supervision for sessions .
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057576_p25
|
39057576
|
sec[2]/sec[2]/sec[5]/p[0]
|
3.3.6. Robotic Therapy
| 1.789063 |
biomedical
|
Other
|
[
0.69580078125,
0.25341796875,
0.050811767578125
] |
[
0.00879669189453125,
0.98779296875,
0.0011911392211914062,
0.0022602081298828125
] |
The ISWP advises that robotic therapy should ideally be considered as part of a clinical trial .
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057576_p26
|
39057576
|
sec[2]/sec[2]/sec[6]/p[0]
|
3.3.7. Virtual Reality/Telerehabilitation
| 1.901367 |
biomedical
|
Other
|
[
0.9189453125,
0.0155029296875,
0.06561279296875
] |
[
0.003177642822265625,
0.98291015625,
0.01299285888671875,
0.0010175704956054688
] |
Virtual reality (VR) is not specifically mentioned by the NICE or ISWP in the context of upper limb therapy, but both guidelines recommend considering telerehabilitation, an umbrella definition for rehabilitation therapies involving technology such as virtual reality devices .
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057576_p27
|
39057576
|
sec[2]/sec[2]/sec[7]/p[0]
|
3.3.8. Other Approaches and Therapeutic Interventions
| 1.541992 |
biomedical
|
Other
|
[
0.84619140625,
0.06378173828125,
0.0899658203125
] |
[
0.006114959716796875,
0.9892578125,
0.0025844573974609375,
0.0020751953125
] |
No advice was offered from the NICE, ISWP or ESO about range-of-motion exercises or biofeedback, or therapies such as acupuncture or non-invasive brain stimulation, in the context of upper limb rehabilitation .
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057576_p28
|
39057576
|
sec[2]/sec[3]/sec[0]/p[0]
|
3.4.1. General Principles and Splinting
| 1.729492 |
biomedical
|
Other
|
[
0.91650390625,
0.0469970703125,
0.036529541015625
] |
[
0.0009441375732421875,
0.99169921875,
0.00545501708984375,
0.0017480850219726562
] |
The NICE and ISWP encourage creating personalised goals for managing spasticity. Both bodies also suggest considering offering and monitoring simple measures to improve spasticity, including arm positioning and passive or active limb movement .
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
39057576_p29
|
39057576
|
sec[2]/sec[3]/sec[1]/p[0]
|
3.4.2. Drug Therapies
| 3.855469 |
biomedical
|
Other
|
[
0.79345703125,
0.194580078125,
0.0119781494140625
] |
[
0.003925323486328125,
0.72314453125,
0.2607421875,
0.0120391845703125
] |
Both the NICE and ISWP guidelines state that botulinum toxin injection response should be monitored and either stopped or continued according to treatment response. Of note, the ISWP also recommends that botulinum should be offered by a specialist multidisciplinary team as an adjunctive therapy alongside usual rehabilitation therapy and/or splinting or casting. The NICE and ISWP additionally recommend monitoring for potential adverse effects of oral anti-spasmodic agents such as baclofen or tizanidine. Furthermore, the ISWP guidelines uniquely mention intrathecal baclofen or intraneural phenol but state they should only be administered by a specialist MDT spasticity service. From a competence perspective, the ISWP and NICE recommend a specialist MDT approach to the assessment, treatment and follow-up of spasticity when using drug therapies .
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057576_p30
|
39057576
|
sec[3]/p[0]
|
4. Discussion
| 3.318359 |
biomedical
|
Review
|
[
0.96044921875,
0.016387939453125,
0.02325439453125
] |
[
0.002227783203125,
0.0244293212890625,
0.9716796875,
0.0014219284057617188
] |
In one document, this review summarises three areas in relation to general approaches to upper limb rehabilitation, technology- and device-assisted rehabilitation, and spasticity management from the NICE, ISWP and ESO guidelines published in 2023.
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
39057576_p31
|
39057576
|
sec[3]/p[1]
|
4. Discussion
| 2 |
biomedical
|
Review
|
[
0.94970703125,
0.0213165283203125,
0.0291290283203125
] |
[
0.0247802734375,
0.39990234375,
0.5712890625,
0.004283905029296875
] |
Collectively, there are only two areas with complete agreement between all three guidelines, namely therapeutic intensity and RTT/TST . However, the UK NICE and ISWP guidelines were found to have a large degree of overlap, such as on recommendations for CIMT, splinting, ES, mirror therapy and VR.
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057576_p32
|
39057576
|
sec[3]/p[2]
|
4. Discussion
| 2.972656 |
biomedical
|
Other
|
[
0.6826171875,
0.27294921875,
0.044525146484375
] |
[
0.0010976791381835938,
0.97509765625,
0.0214996337890625,
0.0023822784423828125
] |
The ISWP and NICE also encourage individualised therapy approaches according to patient needs and available resources and promote the collaboration of a wide range of appropriately trained MDT members to aid stroke survivors in maximising control of pain, improving function and easing care of the upper limbs. The NICE and ISWP also provide information which is setting-specific in relation to the organisation of stroke services and the MDT membership to help clarify where stroke rehabilitation should occur, and which MDT members should be involved . In terms of the target audience, all three guidelines are aimed at researchers, clinical practitioners, stroke survivors and their social networks, with the unified goal of improving stroke care rehabilitation.
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057576_p33
|
39057576
|
sec[3]/p[3]
|
4. Discussion
| 1.645508 |
biomedical
|
Other
|
[
0.63232421875,
0.0361328125,
0.33154296875
] |
[
0.0083160400390625,
0.853515625,
0.1356201171875,
0.0027008056640625
] |
Differences between guidelines are inevitable due to the different approaches and methodologies undertaken by their respective committees or working groups. All three guidelines considered were published in 2023, with evidence being considered between 2016 and 2022 for the ESO, while new evidence was reviewed between 2013 and 2023 for the NICE and 2015 and 2023 for the ISWP .
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057576_p34
|
39057576
|
sec[3]/p[4]
|
4. Discussion
| 3.724609 |
biomedical
|
Other
|
[
0.94384765625,
0.046295166015625,
0.00983428955078125
] |
[
0.0093841552734375,
0.7197265625,
0.267578125,
0.00347137451171875
] |
Apart from clinical guidance, the ISWP and NICE also made research recommendations to help inform future upper limb rehabilitation after stroke that is evidence-based . The NICE makes seven recommendations pertaining to the upper limb, including exploring the clinical and cost-effectiveness of increasing rehabilitation intensity from five to seven days, as well as the interventions to help manage shoulder pain as key research recommendations. Additionally, the NICE recommends identifying the groups of people that would benefit from mirror therapy and researching the clinical and cost-effectiveness of using diagnostic assessment to inform shoulder pain management and exploring the use of acupuncture, botulinum toxin A and electrotherapy for managing spasticity . Similarly, the ISWP makes nine research recommendations relating to upper limb recovery after stroke. These include the effectiveness of functional ES, robotics, mirror therapy, MP, CIMT, RTT, exercise, VNS and intensive arm recovery programmes .
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
39057576_p35
|
39057576
|
sec[3]/p[5]
|
4. Discussion
| 1.907227 |
biomedical
|
Other
|
[
0.90283203125,
0.02154541015625,
0.07550048828125
] |
[
0.00472259521484375,
0.9755859375,
0.0184326171875,
0.001026153564453125
] |
In contrast, the ESO 2023 guidelines do not make any research recommendations about upper limb recovery . However, the ESO previously produced a 2018–2030 Action Plan for Stroke in Europe, which defined 72 research priorities within seven domains, including broad recommendations such as exploring if post-stroke upper limb problems can be more effectively managed .
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
39057576_p36
|
39057576
|
sec[3]/p[6]
|
4. Discussion
| 3.783203 |
biomedical
|
Other
|
[
0.9287109375,
0.06329345703125,
0.00792694091796875
] |
[
0.0077667236328125,
0.79541015625,
0.193603515625,
0.0034732818603515625
] |
Both the ESO and NICE guidelines produce a visual summary to help illustrate the stroke rehabilitation journey, to be used by stroke survivors, their families and social networks and healthcare professionals . Specifically, the NICE has produced a summary involving key questions around stroke rehabilitation, focussing on clinical reviews, therapeutic options, healthcare staff involved in care and assistance with ADLs and returning to the community . The ESO also includes a visual representation of the rehabilitation process in Figure 3 of the guidelines, which includes a cycle of setting goals, considering patient factors, following clinical guidelines, adjusting rehabilitation plans accordingly and using the recommended assessment tools. Unlike the NICE, the ESO visual summary is tailored more towards healthcare professionals and researchers, rather than patients or their social networks .
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057576_p37
|
39057576
|
sec[3]/p[7]
|
4. Discussion
| 1.25293 |
biomedical
|
Other
|
[
0.52001953125,
0.07275390625,
0.4072265625
] |
[
0.0014238357543945312,
0.9951171875,
0.0020599365234375,
0.0012493133544921875
] |
The ISWP has not produced a visual summary. However, it has published a plain-language summary of the national clinical guidelines for stroke, which incorporates key recommendations from the 2023 guideline without jargon, aimed at patients and their social networks .
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057576_p38
|
39057576
|
sec[3]/p[8]
|
4. Discussion
| 2.050781 |
biomedical
|
Other
|
[
0.52392578125,
0.29931640625,
0.177001953125
] |
[
0.0012664794921875,
0.98486328125,
0.01206207275390625,
0.0016078948974609375
] |
Overall, we consider the NICE to be the most informative guideline because it has a wider target audience, includes resources for service providers and commissioners to assist with incorporating guidelines into clinical practise and provides health economic evaluation to ensure that therapeutic recommendations provide good value for money. Additionally, the NICE provides resources aimed at the general public to improve understanding of stroke management and rehabilitation for patients and their social networks. Despite this, the NICE does not address certain therapeutic interventions mentioned by the ISWP or ESO, namely VNS or MP.
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057576_p39
|
39057576
|
sec[3]/p[9]
|
4. Discussion
| 2.25 |
biomedical
|
Other
|
[
0.896484375,
0.04608154296875,
0.057525634765625
] |
[
0.0008096694946289062,
0.98681640625,
0.01136016845703125,
0.00103759765625
] |
Going forward, a consensus between national and international guidelines is required to help establish the most effective therapies and approaches, identify areas of practise which require more research and subsequently make definitive treatment recommendations aiming to improve patient outcomes .
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
39057576_p40
|
39057576
|
sec[3]/p[10]
|
4. Discussion
| 3.886719 |
biomedical
|
Review
|
[
0.9736328125,
0.0181427001953125,
0.0084075927734375
] |
[
0.0019073486328125,
0.0088653564453125,
0.98779296875,
0.0013704299926757812
] |
This review is unique in the context of upper limb stroke rehabilitation, as it collates into one document and compares the recommendations of the ESO, ISWP, and NICE. In addition, this review summarised the clinical recommendations under three distinct categories: approaches, interventions and management of spasticity. The purpose of doing so was to signpost practitioners into relevant areas of stroke that can be more easily identified.
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
39057576_p41
|
39057576
|
sec[3]/p[11]
|
4. Discussion
| 2.699219 |
biomedical
|
Review
|
[
0.94287109375,
0.0122222900390625,
0.044769287109375
] |
[
0.00556182861328125,
0.022308349609375,
0.97119140625,
0.0011682510375976562
] |
However, one of the key limitations is that this review focussed exclusively on guidelines produced by Western nations that were available in English, meaning that guidelines from other regions or published in other languages were not included. It is worth mentioning that one of the authors was a committee member of both NICE and ISWP. Additionally, no third author was invited to review the guidelines, which may have been helpful such as in cases of disagreement between authors. Finally, Table 4 on spasticity management is not inclusive of the individual types of neurotoxins recommended by the guidelines. However, more details about these recommendations can be found in their respective guideline documents .
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999994 |
39057576_p42
|
39057576
|
sec[4]/p[0]
|
5. Conclusions
| 3.818359 |
biomedical
|
Review
|
[
0.96484375,
0.0216522216796875,
0.01331329345703125
] |
[
0.0013799667358398438,
0.0128936767578125,
0.984375,
0.0011129379272460938
] |
Upper limb impairment is common after stroke, with significant impact on the stroke survivor’s function, social participation, and quality of life. This review provides a comprehensive summary of the NICE, ISWP and ESO guidelines published in 2023 for upper limb motor recovery. We believe that while the NICE is more holistic and targets a wider audience, the three guidelines are complimentary. We recommend that a future consensus statement should be developed in partnership between all three organisations, agreeing on scope and using the same terminology, on recommendations to improve stroke rehabilitation in the UK and Europe.
|
[
"Daniel O’Flaherty",
"Khalid Ali"
] |
https://doi.org/10.3390/healthcare12141433
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276629_p0
|
PMC11276629
|
sec[0]/p[0]
|
1. Introduction
| 4.785156 |
biomedical
|
Study
|
[
0.99853515625,
0.0009946823120117188,
0.0004153251647949219
] |
[
0.85546875,
0.0208740234375,
0.1212158203125,
0.0023937225341796875
] |
Bruton’s tyrosine kinase (BTK) is a non-receptor tyrosine kinase representing a crucial signaling node in the B cell receptor (BCR) signaling pathway and plays a pivotal role in B-cell development, activation, and proliferation. BTK belongs to the Tec kinase family and serves as a linchpin in BCR signal transduction. Structurally, BTK comprises distinct domains, including an N-terminal pleckstrin homology (PH) domain crucial for membrane localization, a proline-rich Tec homology (TH) domain implicated in protein–protein interactions, an Src homology 3 (SH3) domain facilitating interactions with proline-rich sequences, an Src homology 2 (SH2) domain involved in substrate recognition, and a C-terminal kinase domain responsible for catalytic activity . Through its intricate domain architecture, BTK translates extracellular stimuli received by the BCR into intracellular signaling events, thus regulating various immune cellular processes .
|
[
"Shefali Mehra",
"Miah Nicholls",
"Justin Taylor"
] |
https://doi.org/10.3390/ijms25147516
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276629_p1
|
PMC11276629
|
sec[0]/p[1]
|
1. Introduction
| 4.226563 |
biomedical
|
Study
|
[
0.99853515625,
0.0008211135864257812,
0.00040030479431152344
] |
[
0.5966796875,
0.337646484375,
0.0633544921875,
0.0020160675048828125
] |
At the forefront of B cell signaling, the BCR pathway orchestrates a cascade of events upon antigen recognition, culminating in cellular responses essential for immune function. The BCR complex consists of membrane-bound immunoglobulin (Ig) molecules that recognize specific antigens, coupled with CD79A and B signaling subunits . Upon antigen binding, the BCR complex undergoes receptor oligomerization and the activation of downstream signaling molecules .
|
[
"Shefali Mehra",
"Miah Nicholls",
"Justin Taylor"
] |
https://doi.org/10.3390/ijms25147516
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276629_p2
|
PMC11276629
|
sec[0]/p[2]
|
1. Introduction
| 4.921875 |
biomedical
|
Study
|
[
0.998046875,
0.0012063980102539062,
0.0005106925964355469
] |
[
0.9580078125,
0.0094451904296875,
0.0310516357421875,
0.0014972686767578125
] |
Central to BCR signaling is the tyrosine kinase Lyn, a member of the Src family of kinases. Lyn is constitutively associated with the cytoplasmic tails of CD79A and CD79B subunits and phosphorylates immunoreceptor tyrosine-based activation motifs (ITAMs) within these subunits upon BCR engagement . Phosphorylated ITAMs serve as docking sites for downstream signaling molecules, including spleen tyrosine kinase (Syk). Syk, a cytoplasmic tyrosine kinase, plays a role in transducing BCR signals upon binding to phosphorylated ITAMs. Structurally, Syk comprises two SH2 domains flanking a catalytic kinase domain. Upon recruitment to phosphorylated ITAMs, Syk undergoes autophosphorylation and activation, initiating downstream signaling cascades . The activation of Syk leads to the phosphorylation and activation of downstream effectors, including phosphoinositide 3-kinase (PI3K) and MAP kinases . PI3K, a heterodimeric enzyme comprising regulatory (p85) and catalytic (p110) subunits, catalyzes the conversion of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3), thereby activating downstream signaling pathways involved in cell survival, proliferation, and metabolism .
|
[
"Shefali Mehra",
"Miah Nicholls",
"Justin Taylor"
] |
https://doi.org/10.3390/ijms25147516
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11276629_p3
|
PMC11276629
|
sec[0]/p[3]
|
1. Introduction
| 4.652344 |
biomedical
|
Study
|
[
0.9990234375,
0.00055694580078125,
0.0002467632293701172
] |
[
0.9833984375,
0.007709503173828125,
0.00832366943359375,
0.0005631446838378906
] |
Within the BCR pathway , BTK occupies a key position downstream of Syk. Upon activation by Syk, BTK undergoes conformational changes and translocation to the cell membrane facilitated by its PH domain. At the membrane, BTK becomes accessible to its substrate molecules and undergoes autophosphorylation at a conserved tyrosine residue within its kinase domain (Y551) . Activated BTK then phosphorylates multiple downstream substrates, thereby propagating the BCR signaling cascade. One of the primary substrates of BTK is phospholipase Cγ2 (PLCγ2), which, upon phosphorylation, leads to its activation. Activated PLCγ2 cleaves PIP2 into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 triggers the release of calcium from intracellular stores, leading to calcium mobilization, while DAG activates protein kinase C (PKC), which in turn regulates various downstream signaling pathways involved in cellular responses .
|
[
"Shefali Mehra",
"Miah Nicholls",
"Justin Taylor"
] |
https://doi.org/10.3390/ijms25147516
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276629_p4
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PMC11276629
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1. Introduction
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Study
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In addition to PLCγ2, BTK activates several other downstream effectors, including MAP kinases such as extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases (JNKs), and p38 MAP kinases. ERKs, a subgroup of MAPKs, are activated downstream of BTK . Upon activation by BTK-mediated phosphorylation, ERKs translocate to the nucleus, where they phosphorylate transcription factors and modulate gene expression programs critical for B-cell activation and function . Furthermore, BTK activation modulates the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway. The phosphorylation of specific NF-κB regulatory proteins downstream of BTK leads to the activation of NF-κB transcription factors, which translocate to the nucleus and regulate the expression of genes involved in immune responses, cell survival, and inflammation .
|
[
"Shefali Mehra",
"Miah Nicholls",
"Justin Taylor"
] |
https://doi.org/10.3390/ijms25147516
|
N/A
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https://creativecommons.org/licenses/by/4.0/
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en
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1. Introduction
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Study
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The interplay between the BTK pathway and other kinases, such as Lyn, Syk, PI3K, and MAP kinases, is integral to the regulation of B-cell signaling and function. Crosstalk between these pathways modulates the intensity and duration of BCR signaling, thereby fine-tuning cellular responses to antigen stimulation .
|
[
"Shefali Mehra",
"Miah Nicholls",
"Justin Taylor"
] |
https://doi.org/10.3390/ijms25147516
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276629_p6
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PMC11276629
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sec[1]/p[0]
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2. BTK and B Cell Lymphoma
| 4.613281 |
biomedical
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Study
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Non-Hodgkin lymphomas (NHLs) represent a diverse array of lymphoid malignancies characterized by the clonal expansion of B or T lymphocytes. The aberrant activation of the BCR pathway stands prominently at the forefront of the pathogenesis of certain B cell NHL subtypes, facilitating uncontrolled B cell proliferation and survival. Dysregulated BCR signaling, often driven by mutations or overexpression of BCR components, engenders the sustained activation of BTK and its downstream effectors. BTK, expressed in all hematopoietic cells except for T cells, intricately regulates critical signaling events downstream of the BCR . Mutations within the BCR complex, such as CD79A/B ITAM mutations, yield constitutive BTK activation, thereby fostering malignant transformation . Kuo et al. were able to determine that a transcription factor, SOX11, was responsible for the hyperactivation of BTK, allowing for tumor development . Moreover, the amplification of BTK expression has been notably observed in diffuse large B-cell lymphoma (DLBCL), correlating with disease aggressiveness and predicting poor prognosis .
|
[
"Shefali Mehra",
"Miah Nicholls",
"Justin Taylor"
] |
https://doi.org/10.3390/ijms25147516
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276629_p7
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PMC11276629
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sec[1]/p[1]
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2. BTK and B Cell Lymphoma
| 4.371094 |
biomedical
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Study
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Furthermore, the crosstalk between the BTK pathway and other signaling cascades significantly contributes to NHL pathogenesis. The activation of NF-κB and MAPK pathways downstream of BTK orchestrates anti-apoptotic gene expression and augments cell survival. Additionally, dysregulated PI3K/Akt signaling, frequently concomitant with BTK activation, fosters cell proliferation and drives metabolic reprogramming in NHL cells .
|
[
"Shefali Mehra",
"Miah Nicholls",
"Justin Taylor"
] |
https://doi.org/10.3390/ijms25147516
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276629_p8
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PMC11276629
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2. BTK and B Cell Lymphoma
| 4.214844 |
biomedical
|
Review
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In summary, the dysregulated BCR pathway assumes a central role in certain NHL pathogenesis, fueling aberrant B-cell proliferation, survival, and migration . Specific alterations in BTK’s regulatory elements, alongside perturbed BCR signaling, collectively contribute to sustained pathway activation and fuel tumor growth. A comprehensive understanding of the intricate mechanisms underpinning BCR-mediated lymphomagenesis not only elucidates the molecular landscape of NHL but also holds promise for the development of novel therapeutic strategies aimed at targeting this pathway for more effective B cell NHL treatment .
|
[
"Shefali Mehra",
"Miah Nicholls",
"Justin Taylor"
] |
https://doi.org/10.3390/ijms25147516
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276629_p9
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PMC11276629
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3. Targeting BTK in B Cell Lymphomas
| 4.390625 |
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The advent of BTK inhibitors ushered in a promising era in lymphoma therapeutics owing to the role played by BTK in the BCR pathway in the pathogenesis of lymphomas. Malignant B-cells exhibit a pronounced reliance on BTK activity for their survival, propelling the pursuit of BTK inhibitors as a targeted therapeutic strategy . Subsequent efforts led to the development of BTK inhibitors such as PCI-32765, heralding a new era in lymphoma therapeutics. PCI-32765, now ibrutinib, emerged as a non-selective and irreversible small molecule inhibitor of BTK . Its mechanism of action involved covalent bonding with the cysteine (Cys)-481 residue at the active site of BTK, resulting in the irreversible inhibition of tyrosine kinase activity at the tyrosine (Tyr)-223 position .
|
[
"Shefali Mehra",
"Miah Nicholls",
"Justin Taylor"
] |
https://doi.org/10.3390/ijms25147516
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
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PMC11276629_p10
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PMC11276629
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3. Targeting BTK in B Cell Lymphomas
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Following the preclinical validation of ibrutinib’s efficacy against malignant B cell proliferation by Honigberg et al., early Phase I trials commenced in 2006 for patients with chronic lymphocytic leukemia (CLL). Given the established link between constant B cell receptor (BCR) activation, mediated by BTK, and CLL pathogenesis, the hypothesis regarding the detrimental impact of BTK inhibition on lymphoma cell survival gained traction. In vitro experiments underscored ibrutinib’s ability to induce apoptosis in CLL cells via caspase activation, coupled with the inhibition of activation-dependent cell proliferation .
|
[
"Shefali Mehra",
"Miah Nicholls",
"Justin Taylor"
] |
https://doi.org/10.3390/ijms25147516
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
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en
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PMC11276629_p11
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3. Targeting BTK in B Cell Lymphomas
| 3.900391 |
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The Phase I trial, encompassing 47 patients with CLL and mantle cell lymphoma (MCL), yielded encouraging results, with three patients achieving complete responses (CRs) and seventeen demonstrating partial responses (PRs). Notably, a significant proportion of patients maintained trial participation for over six months, notwithstanding manageable Grade 3 toxicities, predominantly Grade 3 neutropenia observed in nine patients (19%) .
|
[
"Shefali Mehra",
"Miah Nicholls",
"Justin Taylor"
] |
https://doi.org/10.3390/ijms25147516
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276629_p12
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3. Targeting BTK in B Cell Lymphomas
| 4.09375 |
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Bolstered by favorable responses observed in MCL patients, clinical trials expanded in 2012 to encompass a spectrum of relapsed and refractory non-Hodgkin lymphomas (NHLs) . Advani et al.’s Phase I trial, inclusive of patients with various B cell malignancies, yielded promising outcomes, with 60% of patients achieving either CR or PR, across diverse histologies, including mantle cell, mucosal associated lymphoid tissue, follicular, and DLBCL. Additionally, responses were recorded across all histologies with CRs being seen for patients with MCL (3/9 patients) and follicular lymphoma (3/16 patients) .
|
[
"Shefali Mehra",
"Miah Nicholls",
"Justin Taylor"
] |
https://doi.org/10.3390/ijms25147516
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999993 |
PMC11276629_p13
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PMC11276629
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3. Targeting BTK in B Cell Lymphomas
| 4.25 |
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Study
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The milestone FDA approval of ibrutinib for the treatment of relapsed MCL in 2013 heralded a paradigm shift in lymphoma management . While this approval extended to include treatment for CLL and Waldenström Macroglobulinemia (WM) during the next couple of years, the adverse effects of using a non-selective inhibitor became apparent in many of these clinical trials. While ibrutinib was primarily responsible for targeting BTK, it also inhibited several other kinases, including (Interleukin-2-Inducible T-Cell Kinase) ITK, (Tyrosine Kinase Expressed in Hepatocellular Carcinoma) TEC, and (Tyrosine Kinase Non-Receptor 1) TXK . The inhibition of these kinases resulted in off-target side effects and a higher incidence of adverse events. In trials using ibrutinib as treatment for patients with CLL, MCL, and MCL, up to 16% of patients developed atrial fibrillation as a result. Additionally, patients treated with ibrutinib for CLL, MCL, or WM were found to have a significant 4.85% increased all-grade bleeding risk when compared to control groups, which had 1.1% increased all-grade bleeding risk .
|
[
"Shefali Mehra",
"Miah Nicholls",
"Justin Taylor"
] |
https://doi.org/10.3390/ijms25147516
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11276629_p14
|
PMC11276629
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3. Targeting BTK in B Cell Lymphomas
| 4.636719 |
biomedical
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Review
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Coupled with an increased risk of adverse effects and decreased specificity and targeted inhibition of BTK, the foundation for the development of the next generation of BTK inhibitors was laid. Subsequent approvals of a second generation of BTK inhibitors such as acalabrutinib (formerly ACP-196), orelabrutinib (ICP-022), and zanubrutinib for lymphoma treatment soon followed. These second-generation BTK inhibitors all consisted of altered chemical structures allowing for the increased targeting of the BTK enzyme, when compared to the non-selective ibrutinib. Acalabrutinib, while also being able to covalently bond to the Cys-481 residue like ibrutinib, was able to show greater selectivity for BTK when compared to ibrutinib and has also been approved to treat patients with MCL and CLL. Zanubrutinib, containing a purine core and acrylamide moiety that binds covalently to the cysteine residue (Cys-481) in the BTK enzyme similar to acalabrutinib, has an additional pyrazolo[3,4-d] pyrimidine scaffold which facilitates heightened BTK selectivity. Zanubrutinib has received approval for the treatment of MCL and CLL and is currently being used in clinical trials for patients with WM and DLBCL . The structure of orelabrutinib consists of a distinct scaffold with a urea linkage, allowing it to interact with the BTK active site specifically, and its structure allows for decreased interaction and selectivity for other kinases, thus preventing off-target binding .
|
[
"Shefali Mehra",
"Miah Nicholls",
"Justin Taylor"
] |
https://doi.org/10.3390/ijms25147516
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
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|
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3. Targeting BTK in B Cell Lymphomas
| 4.140625 |
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The results for patients treated with second-generation BTK inhibitors have been promising. Zanubrutinib has shown impressive results in various studies, particularly for relapsed/refractory B-cell lymphomas. In the phase 3 ALPINE trial, zanubrutinib demonstrated superior progression-free survival (PFS) compared to ibrutinib in patients with relapsed/refractory CLL and SLL . Specifically, zanubrutinib reduced the risk of disease progression by 35% and had a 24-month PFS rate of 78.4% compared to 65.9% for ibrutinib. Additionally, zanubrutinib showed a better cardiac safety profile with fewer serious cardiac adverse events compared to ibrutinib . Acalabrutinib has also shown significant efficacy in treating B-cell lymphomas. In the phase 3 ELEVATE-TN trial, acalabrutinib was compared to standard chemoimmunotherapy in previously untreated CLL. Acalabrutinib, either alone or in combination with obinutuzumab, significantly improved PFS compared to chemoimmunotherapy. The study showed that acalabrutinib alone reduced the risk of disease progression or death by 69% compared to chemoimmunotherapy . Finally, in a phase 2 study, patients with relapsed/refractory MCL being treated with orelabrutinib demonstrated a high overall response rate (ORR) of 83% .
|
[
"Shefali Mehra",
"Miah Nicholls",
"Justin Taylor"
] |
https://doi.org/10.3390/ijms25147516
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276629_p16
|
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|
sec[3]/p[0]
|
4. Development of BTK Inhibitor Resistance
| 4.304688 |
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Despite these advancements, resistance and disease progression emerged as formidable challenges among patients receiving covalent BTK inhibitors . Notably, patients with MCL exhibited therapy failure with ibrutinib, and relapsed patients experienced dismal outcomes, typified by a median overall survival of merely 8.4 months post-ibrutinib discontinuation (prior to the development of the BCL-2 inhibitor venetoclax). Furthermore, MCL patients treated with second-generation BTK inhibitors such as acalabrutinib and zanubrutinib also developed resistance to the therapeutics . This led to the development of non-covalent reversible BTK inhibitors (ncBTKis) to address concerns of covalent BTK inhibitor resistance and toxicities. By reversibly binding to BTK via hydrogen or ionic bonding as well as hydrophobic interactions, non-covalent BTK inhibitors do not require C481 in order to elicit their effects . Vecabrutinib was one of the first non-covalent BTK inhibitors developed; however, the CLL program was halted due to a lack of efficacy. Pirtobrutinib and nematabrutinib are orally available, and reversible noncovalent BTK inhibitors that were next to be studied, with pirtobrutinib now gaining approval for relapsed, refractory MCL and CLL. In the BRUIN study, which included CLL, MCL, DLBCL, WM, FL, marginal zone lymphoma (MZL), and primary central nervous system lymphoma (PCNSL), patients treated with pirtobrutinib, formerly LOXO-305, and patients with heavily relapsed and refractory CLL, including those previously treated with BTK inhibitors, were shown to have an overall response rate of 74% .
|
[
"Shefali Mehra",
"Miah Nicholls",
"Justin Taylor"
] |
https://doi.org/10.3390/ijms25147516
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276629_p17
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PMC11276629
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|
4. Development of BTK Inhibitor Resistance
| 4.632813 |
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Despite initial success with treating ibrutinib-resistant lymphomas with non-covalent BTK inhibitors, soon thereafter, studies demonstrated patients experiencing resistance to this new line of therapeutics. While C481 mutations were overcome with non-covalent BTK inhibitors, the discovery of other sites of mutation provided an explanation for resistance in these patients. Mutations in BTK such as C481S and T474I prevent drugs from binding (covalent for C481S and both covalent and non-covalent for T474I) yet allow for continued BTK enzymatic activity. Particular mutations in BTK at C481F, C481Y, C481R, V416L, A428, and L528W have been shown to render the protein kinase-deficient in malignant cells in vitro, hence resulting in inherent resistance to drugs targeting the kinase activity of BTK . Of note, 80% of patients who experience ibrutinib therapy failure have been found to have PLCG2 gene mutations in addition to BTK gene mutations. These mutations result in heightened sensitivity to phosphorylation by BTK and Syk, consequently amplifying the activation of PLCγ2 .
|
[
"Shefali Mehra",
"Miah Nicholls",
"Justin Taylor"
] |
https://doi.org/10.3390/ijms25147516
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276629_p18
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|
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|
4. Development of BTK Inhibitor Resistance
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Other mechanisms of resistance to BTK inhibitors pose a significant challenge in the treatment of NHLs, such as WM. Interestingly, WM patients, who demonstrate MYD88 mutations, were shown to have a 95% response rate to ibrutinib in a study conducted by Castillo et al. . While the reasons for decreased BTK gene mutation mediating resistance to BTK inhibitors for patients with WM remain relatively unexplored, it is thought that CXCR4 mutations may confer resistance to BTK inhibitors instead. Similarly, primary resistance to ibrutinib in MCL often stems from the chronic activation of the MAP3K14-NF-κB pathway, leading to constitutive NF-κB activation. Additionally, mutations in NF-κB inhibitors (TRAF2, TRAF3, BIRC3) contribute to primary resistance, with loss-of-function mutations, particularly in BIRC3, resulting in the activation of non-canonical NF-κB signaling pathways, conferring resistance .
|
[
"Shefali Mehra",
"Miah Nicholls",
"Justin Taylor"
] |
https://doi.org/10.3390/ijms25147516
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
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|
PMC11276629
|
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|
4. Development of BTK Inhibitor Resistance
| 4.351563 |
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|
Study
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Furthermore, mutations in CARD11 downstream of BTK and the regulation of NF-κB activity are also linked to primary resistance to ibrutinib. Chromosomal abnormalities such as chromosome 9p loss containing the SMARCA2 genomic region, deletions in ARID2, or mutations in SMARCA4 have been associated with resistance to ibrutinib . Genetic alterations in chromosomes 9p, 6q, and 13q are commonly observed in ibrutinib-resistant MCL tumors, suggesting their involvement in mediating resistance mechanisms .
|
[
"Shefali Mehra",
"Miah Nicholls",
"Justin Taylor"
] |
https://doi.org/10.3390/ijms25147516
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276629_p20
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4. Development of BTK Inhibitor Resistance
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In addition to genetic factors, non-genetic causes contribute to ibrutinib resistance. Intrinsically, ibrutinib-resistant DLBCL cell lines often exhibit the overexpression of CD79B and the activation of the Akt/MAPK pathway, leading to resistance. MYC overexpression has been identified as an intrinsic cause of ibrutinib resistance in MCL. Furthermore, the activation of non-canonical NF-κB and MAPK pathways through CD40L-CD40 signaling can bypass BTK signaling, diminishing ibrutinib efficacy in MCL. Targeting exportin-1 (XPO1) with selective inhibitors sensitizes intrinsic ibrutinib-resistant MCL cell lines by inhibiting NF-κB signaling .
|
[
"Shefali Mehra",
"Miah Nicholls",
"Justin Taylor"
] |
https://doi.org/10.3390/ijms25147516
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276629_p21
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4. Development of BTK Inhibitor Resistance
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The tumor microenvironment (TME) plays a crucial role in ibrutinib resistance, with stromal cells like mesenchymal stromal cells (MSCs) and myeloid cells promoting tumor growth and resistance. Interaction with MSCs activates the PI3K-mTOR pathway and integrin-β1 signaling, contributing to resistance. The ibrutinib-mediated modulation of the TME involves disrupting oncogenic signaling axes and inhibiting growth-supportive cytokines and growth factors, highlighting the dynamic interplay between the TME and tumor cells in driving resistance mechanisms to BTK inhibitors .
|
[
"Shefali Mehra",
"Miah Nicholls",
"Justin Taylor"
] |
https://doi.org/10.3390/ijms25147516
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276629_p22
|
PMC11276629
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sec[4]/p[0]
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5. Noncatalytic Scaffolding Function of BTK
| 4.320313 |
biomedical
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Study
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The discovery of non-enzymatic functions of BTK began with seminal studies aimed at elucidating the molecular mechanisms underlying X-linked agammaglobulinemia (XLA), a primary immunodeficiency disorder resulting from mutations in the BTK gene. The function of BTK in B cell development independent of its catalytic activity was first outlined by Middendorp et al. by using mice expressing a mutant Btk with a tyrosine to phenylalanine mutation at position 223 (Y223F-Btk) and mice expressing a kinase-inactive mutant Btk with a lysine to arginine mutation at position 430 (K430R-Btk). They were able to determine that Y223 autophosphorylation was not needed for peripheral B cell differentiation and changes in pre B cells; alternatively, kinase-inactive B cells were able to reconstitute B cell activity in BTK-deficient mice as well as partially correct the defective modulation of pre-B cell surface markers, peripheral B cell survival and BCR-mediated NF-kB induction .
|
[
"Shefali Mehra",
"Miah Nicholls",
"Justin Taylor"
] |
https://doi.org/10.3390/ijms25147516
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11276629_p23
|
PMC11276629
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sec[4]/p[1]
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5. Noncatalytic Scaffolding Function of BTK
| 4.242188 |
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Study
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[
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The discovery of the non-enzymatic function of BTK marked a significant milestone in understanding the multifaceted roles of this protein beyond its classical enzymatic activity that allows for the propagation of malignancy. Yuan et al. determined that kinase-inactive forms of BTK in DLBCL cells such as C481F, C481Y, C481R, and L528W maintained BCR signaling . By recreating these unique mutations using CRISPR/Cas9 gene editing in BTK along with transduction into DLBCL cells, Yuan et al. targeted several key genes involved in BCR signaling pathways using signal-guide RNAs (sgRNAs). These genes included CD79A/CD79B, SYK, BLNK, PLCG2, PRKCB, CARD11/BCL10/MALT1, and NFKB1. DLBCL cells harboring BTK-inactivating mutations remained dependent on these BCR signaling pathway genes for continued survival .
|
[
"Shefali Mehra",
"Miah Nicholls",
"Justin Taylor"
] |
https://doi.org/10.3390/ijms25147516
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11276629_p24
|
PMC11276629
|
sec[4]/p[2]
|
5. Noncatalytic Scaffolding Function of BTK
| 4.1875 |
biomedical
|
Study
|
[
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[
0.99951171875,
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Additionally, Yuan et al. found that Toll-like receptor 9 (TLR9), UNC93B1, and CNPY3 formed a protein–protein interaction network in the L528W knock-in DLBCL cells. TLR9 is known for being involved in sensing microbial DNA and triggering proinflammatory signaling, while UNC93B1 and CNPY3 are involved in proper TLR9 folding and localization to endosomes, respectively . They observed the depletion of sgRNAs targeting the nonreceptor tyrosine kinase HCK in L528W knock-in cells. By using a competitive cell growth assay, cells with kinase-inactive BTK (C481F/Y/R and L528W) were depleted more rapidly when transduced with sgRNAs targeting TLR9, UNC93B1, CNPY3, or HCK compared to cells with kinase-active BTK (C481S).
|
[
"Shefali Mehra",
"Miah Nicholls",
"Justin Taylor"
] |
https://doi.org/10.3390/ijms25147516
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11276629_p25
|
PMC11276629
|
sec[4]/p[3]
|
5. Noncatalytic Scaffolding Function of BTK
| 4.265625 |
biomedical
|
Review
|
[
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[
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Transitioning from the discovery of BTK’s non-enzymatic functions to the elucidation of its scaffolding function represented a paradigm shift in the understanding of its molecular mechanisms of action . Initially characterized as a canonical signaling kinase orchestrating phosphorylation-dependent signaling cascades, BTK was later found to act as a molecular scaffold, facilitating protein–protein interactions and the spatial organization of signaling complexes within the cell .
|
[
"Shefali Mehra",
"Miah Nicholls",
"Justin Taylor"
] |
https://doi.org/10.3390/ijms25147516
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276629_p26
|
PMC11276629
|
sec[4]/p[4]
|
5. Noncatalytic Scaffolding Function of BTK
| 4.546875 |
biomedical
|
Study
|
[
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In particular, BTK has been shown to activate integrins downstream of the BCR. Spaargaren et al. demonstrated that BTK activation was necessary for the integrin alpha-4-beta-1 (VLA-4)-mediated adhesion of B cells to vascular cell adhesion molecule −1 and fibronectin. Additionally, BTK was found to play a role in the control of the integrin-mediated adhesion of pre-B cells. This study revealed new roles for BCR and BTK with regard to B cell development and differentiation. The interaction of integrin alpha-4-beta-1 and fibronectin was found to be responsible for controlling early B cell development into pro-, pre-, and immature B cells, which would then play a key role in antigen-specific B cell differentiation. During antigen-specific B cell differentiation, after the formation of germinal centers, wherein B cells would undergo expansion, the representation of antigen by follicular dendritic cells (FDCs) would allow for B cells expressing high affinity BCR for antigen and undergo isotype switching with further maturation into plasma or memory B cells. One of the integrins which mediated the interactions between FDCs and high affinity BCR was found to be alpha-4-beta-1, which engages with vascular cell adhesion protein 1 (VCAM-1) on the FDC. In DT40 cells which were BTK-deficient, Spaargen et al. observed a complete loss of the BCR-mediated adhesion of B cells to VCAM. While these findings provided crucial insights into the canonical enzymatic role of BTK in phosphorylation-mediated signaling pathways, they also hinted at additional functions that remained to be explored .
|
[
"Shefali Mehra",
"Miah Nicholls",
"Justin Taylor"
] |
https://doi.org/10.3390/ijms25147516
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11276629_p27
|
PMC11276629
|
sec[4]/p[5]
|
5. Noncatalytic Scaffolding Function of BTK
| 4.390625 |
biomedical
|
Study
|
[
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[
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One of the seminal findings that underscored the non-enzymatic functions of BTK was its association with actin cytoskeleton remodeling. Not only did BTK have non-enzymatic capabilities with integrin control but also it plays a role in actin skeleton reorganization in order to facilitate the efficient transport and presentation of antigens by B cells . By using a combination of BTK-deficient mice cells and a BTK inhibitor, Sharma et al. demonstrated that actin polymerization was dependent on BTK activity. They observed increased levels of phosphatidyllinositide-4,5-bisphosphonate and phosphorylated Vav, molecules which aid actin cytoskeleton reorganization, upon BCR engagement in a BTK-dependent manner. Furthermore, B cells treated with BTK inhibitors were shown to have late movement to endosomes and delayed BCR internalization. Therefore, through its interaction with actin-binding proteins such as filamin and Nck, BTK was found to modulate cytoskeletal rearrangements critical for cellular processes such as cell adhesion, migration, and phagocytosis .
|
[
"Shefali Mehra",
"Miah Nicholls",
"Justin Taylor"
] |
https://doi.org/10.3390/ijms25147516
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276629_p28
|
PMC11276629
|
sec[4]/p[6]
|
5. Noncatalytic Scaffolding Function of BTK
| 4.375 |
biomedical
|
Study
|
[
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[
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The interactions of BTK with integrins and actin not only highlighted the multifunctional nature of BTK but also demonstrated its involvement in the regulation of fundamental cellular functions independent of its kinase activity. Roman-Garcia et al. detailed the role BTK played in the formation of an antigen-triggered immune synapse (IS formation). Cells with a mutation at the BTK PH domain, preventing BTK transport to the plasma membrane, were observed to have a decreased ability to form IS. It was also determined in vitro that B cells with impaired scaffolding functions would form a peripheral supramolecular activation cluster (pSMAC), the integrin- and F-actin-rich peripheral domain that has an integral role in the stabilization of the IS. Most importantly, they were able to show that a deficiency in the membrane recruitment of BTK was detrimental to the antigen-triggered microtubule-organization center polarization to the IS. Without polarization, in the presence of antigens, B cells with non-catalytic BTK were unable to proliferate .
|
[
"Shefali Mehra",
"Miah Nicholls",
"Justin Taylor"
] |
https://doi.org/10.3390/ijms25147516
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276629_p29
|
PMC11276629
|
sec[4]/p[7]
|
5. Noncatalytic Scaffolding Function of BTK
| 4.570313 |
biomedical
|
Study
|
[
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[
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Finally, further investigations looking into the scaffolding function of BTK includes studies conducted by Montoya et al. where researchers performed the immunoprecipitation of BTK from TMD8 cells overexpressing either wild-type BTK (BTK WT) or the kinase-impaired BTK L528W mutant tagged with a 3X FLAG tag . They then analyzed the interactome of BTK WT and BTK L528W using mass spectrometry to identify proteins uniquely interacting with the mutant BTK L528W. To validate their mass spectrometry findings, the authors performed two-dimensional differential gel electrophoresis (2D-DIGE) analyses followed by the quantitative protein identification of proteins immunoprecipitated from BTK in the knock-in TMD8 cell lines. This orthogonal method confirmed differential protein interactions between wild-type and mutant BTK. The IP/mass spectrometry experiments revealed distinct interactions of BTK L528W with hematopoietic cell kinase (HCK) and integrin-linked kinase (ILK). HCK is a member of the SRC-family tyrosine kinases known to play a role in hematologic malignancies. ILK is a serine/threonine kinase upregulated in malignant cells, implicated in tumorigenesis, cancer cell proliferation, and drug resistance . Ultimately, BTK L528W mutant cells were found to be preferentially dependent on HCK or ILK for cell proliferation and BCR signaling compared with BTK WT cells. BTK mutants resistant to BTK inhibitors achieved this effect by enhancing physical interactions with signaling molecules such as HCK and ILK, bypassing the requirement for BTK phosphorylation at tyrosine 223 to sustain downstream BCR signaling. These findings shed light on a novel mechanism by which BTK mutants confer resistance to BTK inhibitors and sustain downstream BCR signaling through enhanced interactions with signaling molecules such as HCK and ILK .
|
[
"Shefali Mehra",
"Miah Nicholls",
"Justin Taylor"
] |
https://doi.org/10.3390/ijms25147516
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276629_p30
|
PMC11276629
|
sec[5]/p[0]
|
6. Targeting Noncatalytic Functions of BTK
| 3.681641 |
biomedical
|
Other
|
[
0.9990234375,
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[
0.1885986328125,
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The discovery of new functions of BTK revealed a need for new treatment avenues for patients with BTK-dependent lymphomas. Targeting enzyme activity meant that only one aspect of BTK activity would be targeted, which is likely insufficient. Hence, the importance of targeting all aspects of BTK function may help circumvent resistance.
|
[
"Shefali Mehra",
"Miah Nicholls",
"Justin Taylor"
] |
https://doi.org/10.3390/ijms25147516
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276629_p31
|
PMC11276629
|
sec[5]/p[1]
|
6. Targeting Noncatalytic Functions of BTK
| 4.195313 |
biomedical
|
Study
|
[
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[
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Currently, proteolysis-targeting chimeras (PROTACs) have been used to degrade BTK and target the noncatalytic activity of BTK in malignant cells ( Table 1 ). PROTACs are specialized molecules consisting of three parts, a component that binds to the protein of interest (POI), a linker, and a section that binds to E3 ubiquitin ligase . When the PROTAC molecule interacts with both the E3 ligase and the target protein, it forms a complex called POI-PROTAC-E3 ligase. This complex manipulates the ubiquitin–protease system (UPS), leading to the polyubiquitination of the target protein. Subsequently, the protein undergoes proteasomal degradation .
|
[
"Shefali Mehra",
"Miah Nicholls",
"Justin Taylor"
] |
https://doi.org/10.3390/ijms25147516
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276629_p32
|
PMC11276629
|
sec[5]/p[2]
|
6. Targeting Noncatalytic Functions of BTK
| 4.265625 |
biomedical
|
Study
|
[
0.99951171875,
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0.00016021728515625
] |
[
0.92236328125,
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0.044281005859375,
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NX-2127 is at the forefront of novel BTK PROTAC therapeutics being developed, which consists of a heterobifunctional molecule that engages the intracellular ubiquitin–proteasome system to simultaneously bind both BTK and the CRBN E3 ubiquitin ligase complex. This induces polyubiquitination and the subsequent proteasome-dependent degradation of BTK, as well as IKZF1 and IKZF3 proteins. Unlike traditional small-molecule inhibitors, protein degraders harness the cell’s protein degradation machinery to eliminate target proteins, offering advantages in selectivity and prolonged pharmacological effects. IKZF1 (Ikaros) and IKZF3 (Aiolos) are key lymphocyte transcription factors involved in the regulation of cytokines and the proliferation and activation of B cells, T cells, and natural killer cells .
|
[
"Shefali Mehra",
"Miah Nicholls",
"Justin Taylor"
] |
https://doi.org/10.3390/ijms25147516
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276629_p33
|
PMC11276629
|
sec[5]/p[3]
|
6. Targeting Noncatalytic Functions of BTK
| 4.1875 |
biomedical
|
Study
|
[
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[
0.85693359375,
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The degradation of these proteins by NX-2127 has been shown to have therapeutic implications in various B cell malignancies. A total of 23 CLL/SLL patients were enrolled in the Phase I clinical trial across various dose levels. Before treatment with NX-2127, baseline blood specimens from 21 CLL patients were assessed for BTK mutational status. The sequencing analysis revealed a diverse range of mutations, including kinase-impaired mutations (L528W, C481R, and/or V416L) and kinase-proficient mutations (C481S, T474F, and/or T474I). Serial intracellular flow cytometric analysis of BTK degradation in peripheral blood B cells (CD19+CD3−) was performed to assess the kinetics of BTK degradation in patients treated with NX-2127. BTK degradation was quantified using BTK mean fluorescence intensity (MFI) measurements. NX-2127 exposure resulted in BTK degradation in circulating B cells, with maximal degradation observed as early as day 8 of the first cycle. The rate and degree of degradation were similar across all patients, regardless of their mutational status. Furthermore, sustained BTK degradation was observed throughout the daily dosing interval, independent of the mutation type and level of enzymatic activity. The clinical activity of NX-2127 was observed in CLL patients, including those with BTK resistance mutations acquired as a result of prior BTK inhibitor therapies. An improvement in the sum of the product of the diameters (SPD) of target lesions was observed in the majority of evaluable CLL patients (11 out of 14). This improvement was seen in patients harboring both kinase-proficient and kinase-impaired BTK resistance mutations, as well as various other recurrent CLL mutations .
|
[
"Shefali Mehra",
"Miah Nicholls",
"Justin Taylor"
] |
https://doi.org/10.3390/ijms25147516
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11276629_p34
|
PMC11276629
|
sec[5]/p[4]
|
6. Targeting Noncatalytic Functions of BTK
| 3.980469 |
biomedical
|
Study
|
[
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[
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Another PROTAC being investigated in adults with relapsed/refractory B cell malignancies is NX-5948, which selectively degrades BTK and not IKZF1/3 . Currently, seven patients have been enrolled in phase 1a, receiving doses of 50 mg or 100 mg. Preliminary results indicate that NX-5948 exhibits dose-proportional pharmacokinetics, with a half-life of approximately 12 h and rapid, robust, and sustained degradation of BTK observed in all patients .
|
[
"Shefali Mehra",
"Miah Nicholls",
"Justin Taylor"
] |
https://doi.org/10.3390/ijms25147516
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276629_p35
|
PMC11276629
|
sec[5]/p[5]
|
6. Targeting Noncatalytic Functions of BTK
| 4.070313 |
biomedical
|
Other
|
[
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[
0.35302734375,
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Another PROTAC for BTK is being tested in the BGB-16673-101 trial, an open-label, phase 1 study evaluating the safety, tolerability, and efficacy of BGB-16673 in patients with relapsed/refractory B cell malignancies, including CLL, WM, MCL, MZL, non-germinal center B-cell DLBCL, FL, and RT. Patients must have received at least two prior therapies (except for RT) and have an ECOG performance status of 0–2. The study utilizes dose escalation with six planned dose levels (50–600 mg once daily) using a Bayesian optimal interval design. Primary objectives include assessing safety, establishing the maximum tolerated dose (MTD), and determining the recommended phase 2 dose. Secondary objectives involve evaluating pharmacokinetics, pharmacodynamics, and preliminary antitumor activity. As of 26 May 2023, 26 patients have been enrolled across five dose levels. The median age was 70.5 years, and the median number of prior therapies was 3.5. Most patients had received prior covalent BTK inhibitors. Treatment-emergent adverse events (TEAEs) were common, with the most frequent being contusion, pyrexia, neutropenia, and increased lipase levels. No dose-limiting toxicities were observed, and the MTD was not reached. BGB-16673 exposure increased with dose, and preliminary pharmacodynamic data showed significant reductions in BTK protein levels in both peripheral blood and tumor tissue. Most CLL patients experienced lymphocytosis during treatment. Of the response-evaluable patients, 67% responded to treatment, including patients previously treated with covalent or non-covalent BTK inhibitors. The responses were durable, with the longest responder remaining on treatment for 60 weeks .
|
[
"Shefali Mehra",
"Miah Nicholls",
"Justin Taylor"
] |
https://doi.org/10.3390/ijms25147516
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276629_p36
|
PMC11276629
|
sec[6]/p[0]
|
7. Conclusions and Future Directions
| 4.753906 |
biomedical
|
Review
|
[
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[
0.26806640625,
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The B cell receptor (BCR) signaling pathway and its central mediator, Bruton’s tyrosine kinase (BTK), regulate immune responses in normal hematopoietic cells but can contribute to lymphomagenesis. The activation of BTK via the BCR causes signal transduction to mediators of cellular processes critical for B cell function and survival. The pivotal role of BTK in BCR signaling and B cell lymphoma pathogenesis has led to the development of BTK inhibitors as targeted therapies, which are now a frontline therapy for many lymphoma subtypes. Ibrutinib, the first FDA-approved BTK inhibitor, has demonstrated remarkable efficacy in treating relapsed/refractory MCL, CLL, and other B-cell malignancies. Subsequent generations of BTK inhibitors, such as acalabrutinib and zanubrutinib, offer enhanced selectivity and efficacy, expanding treatment options for patients. Despite the development of non-covalent BTK inhibitors, such as pirtobrutinib, in order to overcome C481 BTK resistance mutations seen after covalent BTK inhibition, newly discovered kinase-deficient BTK resistance mutations seen after covalent and noncovalent BTK inhibitor treatment prompted further investigations into BTK’s scaffold function.
|
[
"Shefali Mehra",
"Miah Nicholls",
"Justin Taylor"
] |
https://doi.org/10.3390/ijms25147516
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276629_p37
|
PMC11276629
|
sec[6]/p[1]
|
7. Conclusions and Future Directions
| 4.191406 |
biomedical
|
Review
|
[
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[
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The emergence of resistance to covalent and non-covalent BTK inhibitors poses a significant clinical challenge, necessitating a deeper understanding of resistance mechanisms and the development of novel therapeutic strategies. Efforts to target the noncatalytic scaffolding functions of BTK, alongside its enzymatic activity, offer promising avenues for overcoming resistance and improving patient outcomes. Innovative approaches, including protein degraders like PROTACs, such as NX-2127, NX-5948, and BGB-16673, represent a novel approach to target BTK and IKZF1/3 proteins, offering potential benefits in the treatment of B cell malignancies, including those resistant to traditional small-molecule inhibitors. When comparing PROTACS to BTK inhibitors, there are also different pharmacokinetic stoichiometries, with one PROTAC molecule being able to degrade multiple BTK molecules. Ultimately, the choice between these molecules will be heavily influenced by clinical trial outcomes, including efficacy, safety profiles, and any observed resistance mechanisms with the PROTACs.
|
[
"Shefali Mehra",
"Miah Nicholls",
"Justin Taylor"
] |
https://doi.org/10.3390/ijms25147516
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
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|
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|
7. Conclusions and Future Directions
| 3.962891 |
biomedical
|
Review
|
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By targeting the multifaceted functions of BTK and its interplay with the tumor microenvironment, researchers strive to optimize therapeutic strategies and improve outcomes for patients with B-cell malignancies. While there is an inherent need for trials to expand and include patients with other types of B cell lymphomas, the discovery of additional scaffolding functions for BTK in addition to novel therapeutics targeting these functions will offer new options for clinicians treating patients with malignancies relapsed and refractory to current BTK inhibitors.
|
[
"Shefali Mehra",
"Miah Nicholls",
"Justin Taylor"
] |
https://doi.org/10.3390/ijms25147516
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276641_p0
|
PMC11276641
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|
1. Introduction
| 2.648438 |
biomedical
|
Other
|
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[
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Drought is currently one of the most serious global problems threatening crop growth and productivity , and its global crop losses may exceed those caused by all other abiotic stresses combined . In response to environmental stimuli, plants balance water loss by optimizing stomatal opening and closing .
|
[
"Xue Li",
"Shiwen Zhao",
"Qianqian Cao",
"Chun Qiu",
"Yuanyuan Yang",
"Guanzhi Zhang",
"Yongjun Wu",
"Zhenchao Yang"
] |
https://doi.org/10.3390/ijms25147561
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
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1. Introduction
| 4.402344 |
biomedical
|
Study
|
[
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Stomata consist of paired guard cells in the plant epidermis that act as windows between the plant and the external environmental gases, and plants respond to various environmental stimuli through changes in guard cell volume expansion, which leads to stomatal opening and closing . Stomatal opening increases photosynthetic CO 2 uptake to promote plant growth and dissipates water through transpiration . Stomatal movement is regulated by various factors such as light, temperature, and CO 2 . Therefore, it has been proposed to improve photosynthesis and water use efficiency by changing environmental conditions so that the stomatal response rate is increased . However, by increasing CO 2 conductance by increasing stomatal conductance, this will inevitably cause a synergistic increase in transpiration rate, which will result in a large amount of water dissipation from the plant, and when the leaf water potential is reduced to a certain threshold, the leaf will close the stomata to prevent further water dissipation . Therefore, the synergy between stomatal conductance and leaf water transport capacity is important to maintain the balance of leaf water supply and loss and to ensure that leaf tissues undergo normal photosynthesis .
|
[
"Xue Li",
"Shiwen Zhao",
"Qianqian Cao",
"Chun Qiu",
"Yuanyuan Yang",
"Guanzhi Zhang",
"Yongjun Wu",
"Zhenchao Yang"
] |
https://doi.org/10.3390/ijms25147561
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
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1. Introduction
| 4.308594 |
biomedical
|
Study
|
[
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Cryptochrome and photosensitizer work in concert to mediate stomatal opening . Under low doses of blue light, cryptophycin and photosensitizer act on COP1 and abscisic acid (ABA), respectively, to activate guard cell plasma membrane H + -ATPases. These H + -ATPases pump H + to the outside of the plasma membrane, resulting in a positive (external) to negative (internal) potential gradient that leads to the influx of K + ions into the membrane. Green light, on the other hand, inactivates cryptochrome , thus eliminating the inhibition of ABA production signals in guard cells and promoting a reduction in stomatal aperture. Furthermore, Frechilla et al. found that green light at 490 to 580 nm reversed blue-light-induced stomatal opening in isolated epidermis, which is consistent with the results of a study by Talbott et al.’s findings . In both studies, the degree of reversal was irradiance-dependent at continuous irradiance, with complete reversal when green light was twice as much as blue light. Further studies have shown that the same response can be observed in Arabidopsis leaves , and the work of also concluded that green light (λ500–600 nm) exposure reversibly reduces stomatal conductance in lettuce. Green light signals play an important role in controlling stomatal aperture and the balance between water loss and CO 2 uptake within the canopy, so the antagonistic nature of the green light response to blue light implies that the stomata are responsive to the B:G ratio, which should provide signals that can be fine-tuned in a way that may be beneficial to the plant in balancing the efficiency of photosynthesis and water use within the dense canopy. The present study investigated the effects of different red/blue/green ratios on photosynthesis and stomatal characteristics of melon ( Cucumis melo ) seedlings, aiming to provide some implications for improving plant water utilization by altering light quality.
|
[
"Xue Li",
"Shiwen Zhao",
"Qianqian Cao",
"Chun Qiu",
"Yuanyuan Yang",
"Guanzhi Zhang",
"Yongjun Wu",
"Zhenchao Yang"
] |
https://doi.org/10.3390/ijms25147561
|
N/A
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https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
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2.1. The Effect of Green Light Replacing Some Red and Blue Light on the Morphology of Melon Seedlings under Drought Stress
| 3.923828 |
biomedical
|
Study
|
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Seedling morphological indexes were determined on the 9th day of drought, and as shown in Table 1 , plant height, fresh weight, dry weight, and total leaf area changed significantly with the increase in green light percentage. Plant height was significantly higher in the T3 treatment than in the rest of the treatments. The plant height at T3 was significantly higher than the rest of the treatments, and the plant height at T3 was significantly increased by 28.90%, 27.09%, and 13.47% compared to the CK, T1, and T2 treatments, respectively. Fresh weight was significantly higher in the T3 treatment than in the rest of the treatments. The fresh weight under the T3 treatment was significantly higher than the rest of the treatments, being 55.50%, 61.56%, and 33.69% higher than the CK, T1, and T2 treatments, respectively. The fresh weight under the T3 treatment was significantly higher than the CK, T1, and T2 treatments by 55.50%, 61.56%, and 33.69%. The dry weight was highest under the T3 treatment, which was significantly higher than that of the CK treatment by 30.15%, but there was no significant difference among the three treatments, namely, T1, T2, and T3. There was no significant difference between the three treatments of T1, T2 and T3.
|
[
"Xue Li",
"Shiwen Zhao",
"Qianqian Cao",
"Chun Qiu",
"Yuanyuan Yang",
"Guanzhi Zhang",
"Yongjun Wu",
"Zhenchao Yang"
] |
https://doi.org/10.3390/ijms25147561
|
N/A
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https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
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2.2. Effect of Green Light Replacing Some Red and Blue Light on Photosynthetic Characteristics of Melon Seedlings under Drought Stress
| 4.113281 |
biomedical
|
Study
|
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Transpiration rate (E), stomatal conductance (gsw), intercellular CO 2 (Ci), and net photosynthesis rate (Pn) were measured on day 3, day 6, and day 9 of the drought treatments, respectively. E was highest and significantly higher under the CK treatment than the T2 and T3 treatments on day 3 of the treatment, but significantly lower than the remaining treatments on day 6 of the treatment . At treatment d 3, gsw was significantly higher under CK treatment but significantly lower than the rest of the treatments at d6 . There was no significant difference in Ci among treatments on day 3, but on day 6 and day 9, the CK treatment values were lower than the remaining treatments . Pn was significantly higher under T1 and T2 treatments than CK and T3 on day 3, but on d 6 and 9, the CK treatment of Pn was significantly lower than the rest of the treatments, and there was no significant difference between T1, T2, and T3 .
|
[
"Xue Li",
"Shiwen Zhao",
"Qianqian Cao",
"Chun Qiu",
"Yuanyuan Yang",
"Guanzhi Zhang",
"Yongjun Wu",
"Zhenchao Yang"
] |
https://doi.org/10.3390/ijms25147561
|
N/A
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https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
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2.3. Effect of Green Light Replacing Some Red and Blue Light on Stomatal Aperture and REC of Melon Seedlings under Drought Stress
| 4.089844 |
biomedical
|
Study
|
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The data of stomatal measurement on the 9th day are shown in Table 2 . The short-term light treatment with different wavelengths had no significant effect on the length and width of stomata under different treatments, but the effects on pore length, pore width, and pore area were quite different. The pore widths of the T2 and T3 treatments were significantly decreased by 22.66% and 33.14% compared with that of the CK treatment, but there was no significant difference between the T1 and CK treatments. The pore length of the CK treatment was significantly higher than the rest of the treatments, and the pore length of the CK treatment was significantly increased by 15.78%, 16.24%, and 12.97% compared with T1, T2, and T3 treatments, respectively; due to the differences in the pore length and width of the treatments, the pore area of the treatments also differed, in which the pore area of T2 and T3 treatments was significantly decreased by 8.31% and 8.81% compared with that of the CK treatment, respectively.
|
[
"Xue Li",
"Shiwen Zhao",
"Qianqian Cao",
"Chun Qiu",
"Yuanyuan Yang",
"Guanzhi Zhang",
"Yongjun Wu",
"Zhenchao Yang"
] |
https://doi.org/10.3390/ijms25147561
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276641_p6
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2.3. Effect of Green Light Replacing Some Red and Blue Light on Stomatal Aperture and REC of Melon Seedlings under Drought Stress
| 3.699219 |
biomedical
|
Study
|
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Seedling leaf electrolyte osmolality was determined at 3, 6, and 9 days . The relative electrolyte osmolality of each treatment increased significantly at d 6 compared to the ground on day 3 with increasing drought treatment time. Only the T3 treatment was significantly lower than the remaining treatments at day 3. At treatments on day 6 and day 9, T1, T2, and T3 were significantly lower than the CK treatments, with the T3 treatment being the most significant.
|
[
"Xue Li",
"Shiwen Zhao",
"Qianqian Cao",
"Chun Qiu",
"Yuanyuan Yang",
"Guanzhi Zhang",
"Yongjun Wu",
"Zhenchao Yang"
] |
https://doi.org/10.3390/ijms25147561
|
N/A
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https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11276641_p7
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2.4. Effect of Green Light Replacing Some Red and Blue Light on MDA and SOD in Leaves of Melon Seedlings under Drought Stress
| 3.8125 |
biomedical
|
Study
|
[
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[
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The MDA content of each treatment was determined on the 9th day of drought, and T1, T2, and T3 were significantly lower than the CK treatment, and the T3 treatment was the most significant. There was no significant difference between T1 and T2 treatment groups . As the proportion of green light substitution increased, the SOD activity of each treatment showed a significant increasing trend; CK, T2, and T3 were significantly lower than the T3 treatment, and there was no significant difference between T1 and T2 treatment groups .
|
[
"Xue Li",
"Shiwen Zhao",
"Qianqian Cao",
"Chun Qiu",
"Yuanyuan Yang",
"Guanzhi Zhang",
"Yongjun Wu",
"Zhenchao Yang"
] |
https://doi.org/10.3390/ijms25147561
|
N/A
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https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11276641_p8
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2.5. Effect of Green Light Replacing Some Red and Blue Light on H 2 O 2 and O 2 ∙− in Leaves of Melon Seedlings under Drought Stress
| 3.966797 |
biomedical
|
Study
|
[
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With the increase in the proportion of green light substitution, the H 2 O 2 content of each treatment showed a significant decreasing trend; T1, T2, and T3 were all significantly lower than the CK treatment, the T3 treatment was the most significant, there was no significant difference between the T1 and T2 treatment groups , and the results of the DAB staining of melon seedling leaves under each treatment were consistent . For the O 2 ∙− content of melon seedling leaves under each treatment obtained as in Figure 3 c, T2 and T3 were significantly lower than the CK treatment, but there was no significant difference between the T1 and CK treatment groups, and the NBT staining results of melon seedling leaves under each treatment were consistent .
|
[
"Xue Li",
"Shiwen Zhao",
"Qianqian Cao",
"Chun Qiu",
"Yuanyuan Yang",
"Guanzhi Zhang",
"Yongjun Wu",
"Zhenchao Yang"
] |
https://doi.org/10.3390/ijms25147561
|
N/A
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https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11276641_p9
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sec[1]/sec[5]/sec[0]/p[0]
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2.6.1. RNA-Seq Analysis
| 4.039063 |
biomedical
|
Study
|
[
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The sequenced RNA-seq libraries ranged in size from 41,980,568 bp to 42,519,908 ( Table S2 ), and the Q30 percentage (percentage of sequences with <0.1% errors) for each library was >97.45%. Overall, the RNA-seq data were of high quality and could be used for further analysis.
|
[
"Xue Li",
"Shiwen Zhao",
"Qianqian Cao",
"Chun Qiu",
"Yuanyuan Yang",
"Guanzhi Zhang",
"Yongjun Wu",
"Zhenchao Yang"
] |
https://doi.org/10.3390/ijms25147561
|
N/A
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https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11276641_p10
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2.6.2. Identification of Differentially Expressed Genes (DEGs) between Groups
| 4.042969 |
biomedical
|
Study
|
[
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In order to further investigate the key genes involved in the regulation of drought tolerance in melon seedlings under different treatments, this study analyzed the transcriptome of plant leaves under CK and T3 treatments after 9 d of drought. There were a total of 1260 DEGs (Differential Expression Analysis, DEG), with 591 up-regulated DEGs and 723 down-regulated DEGs in T3 compared with the CK treatment , and the heatmap analysis of the differential genes is shown in Figure 4 a.
|
[
"Xue Li",
"Shiwen Zhao",
"Qianqian Cao",
"Chun Qiu",
"Yuanyuan Yang",
"Guanzhi Zhang",
"Yongjun Wu",
"Zhenchao Yang"
] |
https://doi.org/10.3390/ijms25147561
|
N/A
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https://creativecommons.org/licenses/by/4.0/
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en
| 0.999998 |
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2.6.3. GO Pathway Annotation Analysis of Differential Genes
| 4.082031 |
biomedical
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Study
|
[
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[
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] |
The top 20 GO entries with the smallest p -value were plotted with the GO entry in the vertical coordinate and the −log10 value of the p or Q value of the enrichment analysis for that GO entry in the horizontal coordinate, and the results are shown in Figure 4 b. In the comparison between T3 and CK, the DNA-binding transcription factor activity , transcriptionally regulated DNA template , and alginate phosphatase were the first three significantly different GO pathways. There were 134, 139, and 8 genes involved in these three significantly enriched pathways, respectively.
|
[
"Xue Li",
"Shiwen Zhao",
"Qianqian Cao",
"Chun Qiu",
"Yuanyuan Yang",
"Guanzhi Zhang",
"Yongjun Wu",
"Zhenchao Yang"
] |
https://doi.org/10.3390/ijms25147561
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https://creativecommons.org/licenses/by/4.0/
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en
| 0.999997 |
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2.6.4. KEGG Pathway Annotation Analysis of Differential Genes
| 4.125 |
biomedical
|
Study
|
[
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] |
To further explore the biological functions of DEGs, pathway enrichment analysis was performed based on the KEGG database, and the results are presented in the form of an enrichment scatterplot. The KEGG enrichment scatterplot showed that phytohormone signaling , flavonoids and flavonols biosynthesis , and α-linolenic acid pronuclei were the three pathways with the highest enrichment degree. Among them, 21 genes were significantly up-regulated and 31 genes were significantly down-regulated in the phytohormone signaling pathway; 3 genes were significantly up-regulated and 6 genes were significantly down-regulated in the flavonoids and flavonols biosynthesis pathway; and 9 genes were significantly up-regulated and 6 genes were significantly down-regulated in the α-linolenosuccinate substitution pathway .
|
[
"Xue Li",
"Shiwen Zhao",
"Qianqian Cao",
"Chun Qiu",
"Yuanyuan Yang",
"Guanzhi Zhang",
"Yongjun Wu",
"Zhenchao Yang"
] |
https://doi.org/10.3390/ijms25147561
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https://creativecommons.org/licenses/by/4.0/
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| 0.999998 |
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2.6.5. Analysis of Plant Hormone Synthesis Pathways
| 4.085938 |
biomedical
|
Study
|
[
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[
0.99951171875,
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] |
The analysis revealed that “phytohormone signaling” was an important pathway in response to light quality changes under drought stress when green light replaced part of the red and blue light in the spectrum compared with red and blue light. The results showed that several hormone signaling pathways, including growth hormone (IAA), cytokinin (CK), gibberellin (GA), abscisic acid (ABA), salicylic acid (SA), brassinosteroid (BR), jasmonic acid (JA), and ethylene (ETH), were affected by the light quality changes. Among them, 7 out of 15 differential genes related to ABA, JA, SA, GA, and BR signaling showed an up-regulation trend under the T3 treatment compared with the CK treatment .
|
[
"Xue Li",
"Shiwen Zhao",
"Qianqian Cao",
"Chun Qiu",
"Yuanyuan Yang",
"Guanzhi Zhang",
"Yongjun Wu",
"Zhenchao Yang"
] |
https://doi.org/10.3390/ijms25147561
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N/A
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https://creativecommons.org/licenses/by/4.0/
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en
| 0.999997 |
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2.6.6. qRT-PCR Validation
| 3.861328 |
biomedical
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Study
|
[
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The reliability of the RNA-Seq data was verified by qRT-PCR using nine randomly selected differential genes . The results showed that most of the gene expression trends in the qRT-PCR data were similar to the transcriptome results, and these results confirmed the reliability of the RNA-Seq data.
|
[
"Xue Li",
"Shiwen Zhao",
"Qianqian Cao",
"Chun Qiu",
"Yuanyuan Yang",
"Guanzhi Zhang",
"Yongjun Wu",
"Zhenchao Yang"
] |
https://doi.org/10.3390/ijms25147561
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https://creativecommons.org/licenses/by/4.0/
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en
| 0.999998 |
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2.7.1. Differential Metabolite Statistics
| 4.058594 |
biomedical
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Study
|
[
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[
0.99951171875,
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] |
To further investigate the changes of hormone-related metabolites in melon seedlings after the green light replaced part of the red and blue light treatments, we performed a metabolomic analysis of melon seedling leaves using LC-MS. The results of the metabolomic analysis of melon seedling leaves using LC-MS indicated that a total of 103 significantly different metabolites were detected, with 44 metabolites significantly up-regulated and 59 metabolites significantly down-regulated in the T3 treatment compared with the CK treatment .
|
[
"Xue Li",
"Shiwen Zhao",
"Qianqian Cao",
"Chun Qiu",
"Yuanyuan Yang",
"Guanzhi Zhang",
"Yongjun Wu",
"Zhenchao Yang"
] |
https://doi.org/10.3390/ijms25147561
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N/A
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https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
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2.7.1. Differential Metabolite Statistics
| 2.878906 |
biomedical
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Study
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[
0.99658203125,
0.0005350112915039062,
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] |
[
0.99755859375,
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] |
The metabolites were first analyzed by PCA using the principal component analysis (PCA) model , and we found that the accumulation of metabolites in the T3 and CK treatments was significantly different.
|
[
"Xue Li",
"Shiwen Zhao",
"Qianqian Cao",
"Chun Qiu",
"Yuanyuan Yang",
"Guanzhi Zhang",
"Yongjun Wu",
"Zhenchao Yang"
] |
https://doi.org/10.3390/ijms25147561
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N/A
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https://creativecommons.org/licenses/by/4.0/
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en
| 0.999998 |
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2.7.2. Differential Metabolites KEGG Functional Annotation
| 4.003906 |
biomedical
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Study
|
[
0.9990234375,
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[
0.99951171875,
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0.00021898746490478516,
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] |
For differential metabolites, KEGG pathway analysis was performed. The top 20 pathways with the smallest p -value were taken for bubble plot presentation, and the results are shown in Figure 6 b. The KEGG enrichment scatter plot showed that the biosynthesis of plant secondary metabolites , the biosynthesis of plant hormones , and the biosynthesis of amino acid compounds were the three pathways with the highest degree of enrichment.
|
[
"Xue Li",
"Shiwen Zhao",
"Qianqian Cao",
"Chun Qiu",
"Yuanyuan Yang",
"Guanzhi Zhang",
"Yongjun Wu",
"Zhenchao Yang"
] |
https://doi.org/10.3390/ijms25147561
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276641_p18
|
PMC11276641
|
sec[1]/sec[6]/sec[2]/p[0]
|
2.7.3. Analysis of Differential Metabolites for Plant Hormone Synthesis
| 3.863281 |
biomedical
|
Study
|
[
0.9970703125,
0.00026679039001464844,
0.0024566650390625
] |
[
0.9990234375,
0.0005283355712890625,
0.00020575523376464844,
0.000048279762268066406
] |
Phytohormones are widely involved in the plant response to external environmental stress, and stomatal opening and closing in plants are regulated by a variety of phytohormones. Therefore, we selected the differential metabolites within the biosynthesis of phytohormones for analysis, and there were 13 differential metabolites, which showed that aspartic acid and jasmonic acid were significantly up-regulated under the T3 treatment compared with the CK treatment, and citric acid, α-D-glucose, tryptophan, and AMP were significantly down-regulated under the T3 treatment compared with the CK treatment. .
|
[
"Xue Li",
"Shiwen Zhao",
"Qianqian Cao",
"Chun Qiu",
"Yuanyuan Yang",
"Guanzhi Zhang",
"Yongjun Wu",
"Zhenchao Yang"
] |
https://doi.org/10.3390/ijms25147561
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11276641_p19
|
PMC11276641
|
sec[2]/sec[0]/p[0]
|
3.1. Effects of Green Light Replacing Some Red and Blue Light on the Morphology and Photosynthesis of Melon Seedlings under Drought Stress
| 4.105469 |
biomedical
|
Study
|
[
0.9892578125,
0.0004336833953857422,
0.01015472412109375
] |
[
0.9990234375,
0.00022327899932861328,
0.0005121231079101562,
0.00003898143768310547
] |
Light plays a significant role in plant growth, development, and stress response . It is known that photoreceptors for red and blue light exist in plants and that chlorophyll in plants is effective in absorbing red and blue light. However, in recent years, studies have shown that green light also plays a key role in plant growth and can improve the ability of plants to cope with abiotic stresses . In this experiment, melon seedlings were placed under treatments with different light qualities and short-term drought stress when they grew to three leaves and one heart. The experimental results showed that green light replacing part of the red and blue light treatments could alleviate the drought stress of the plants to a certain extent and keep the melon seedlings maintaining a relatively high photosynthetic capacity. With the increase in the proportion of green light, melon seedlings had significant changes in their plant height, fresh weight, dry weight, and total leaf area, and the above indexes were significantly better than the CK treatment under the T3 treatment, which was consistent with the results of the experiments conducted by Bian et al. on tomato seedlings and Ma et al. on cucumber seedlings .
|
[
"Xue Li",
"Shiwen Zhao",
"Qianqian Cao",
"Chun Qiu",
"Yuanyuan Yang",
"Guanzhi Zhang",
"Yongjun Wu",
"Zhenchao Yang"
] |
https://doi.org/10.3390/ijms25147561
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
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