A comprehensive understanding of the mechanisms coupling cell cycle exit and differentiation is important for both cancer biology and tissue development. Cancer cells can arise from either ...stem/progenitor cells that fail to exit the cell cycle and differentiate, or from de-differentiated cells that have re-entered the cell cycle. Much of our current understanding of this coupling is based on observations made in transformed cell lines. These studies have shown that enforcing proliferation prevents differentiation and inducing growth arrest leads to differentiation; thus, one widely-held view is that changes in cell cycle regulators simply induces cell cycle exit, a pre-requisite for differentiation. However, recent evidence indicates that cell cycle regulators can affect differentiation in other ways as well. They can have a role establishing the new transcriptional program that accompanies differentiation-in its most radical form, the molecular mechanism of arrest might even be an integral component of the differentiation program. Additionally, the regulators or mechanisms that prevent the re-entry of cells into the proliferative cycle may not be those that induce exit from the cell cycle. Our goal in this perspective is to highlight examples from our laboratory that provided a broader understanding of the types of roles that cell cycle regulators play during differentiation, beginning with the phenotypes observed in mice.
Abstract Objective To report our clinical experience and propose a biomechanical factor–based treatment strategy for improvement of genu recurvatum (GR) to reduce the need for knee-ankle-foot ...orthosis (KAFO) or surgical treatment. Design Case series. Setting Outpatient clinic of a Department of Physical Medicine and Rehabilitation in an academic medical center. Subjects and Interventions Adult subjects (n = 22) with hemiparesis and GR who received botulinum injections alone or in combination with multiple types of orthotic interventions that included solid ankle-foot orthosis (AFO) ± heel lift, hinged AFO with an adjustable posterior stop ± heel lift, AFO with dual-channel ankle joint ± heel lift, or KAFO with offset knee joint. Biomechanical factors reviewed included muscle strength, modified Ashworth score for spasticity, presence of clonus, posterior capsule laxity, sensory deficits, and proprioception. Outcome Measurements Outcome factors were improvement or elimination of GR based on subjective assessment before and after the interventions by the same experienced clinician. Results More than one biomechanical factor contributed to GR in all patients. Botulinum toxin A injection was used in patients who had significant plantar flexor spasticity and/or clonus. Four types of orthotic interventions were used based on the biomechanical factor: solid AFO in patients with severe ankle dorsiflexion and plantar flexion weakness or clonus; hinged ankle joint with adjustable posterior stop in patients with less severe ankle dorsiflexion weakness in the absence of clonus; AFO with a dual-channel ankle joint for quadriceps weakness or severe proprioceptive deficits; and KAFO with offset knee joints in patients with Achilles tendon contracture or severe proprioceptive deficits. Adjunctive options included the addition of heel lifts and toeplate modifications. Combinatorial interventions of botulinum injection, modified AFOs, and heel lifts improved or eliminated GR and avoided the need for cumbersome orthotics or surgical interventions. Conclusions GR in hemiparesis is multifactorial and can be successfully controlled by using a conservative biomechanical factor–based approach and combined medical and orthotic interventions. An algorithmic approach and a prospective study design is proposed to determine a combination of effective interventions to correct GR.
CONTEXTSpinal cord injury (SCI) presents significant challenges due to its debilitating nature and potential complications. While few medications have shown efficacy in improving neurological ...recovery, 4-Aminopyridine (4-AP), a voltage-gated potassium channel blocker, has been used clinically off-label to improve neurologic function in adults with spinal cord-related paralysis. However, evidence regarding its safety and effectiveness in the pediatric population remains scarce, as it is approved for use in older patients.FINDINGSThis manuscript reports the case of a pediatric patient who sustained a traumatic cervical SCI. Initial neurological assessment indicated a C1 motor complete SCI. Surgical intervention for bullet removal and spinal fusion was carried out, followed by comprehensive inpatient rehabilitation.CONCLUSION/CLINICAL RELEVANCE4-AP was introduced three months post-injury and was well-tolerated without obvious adverse effects. Notably, he exhibited neurological and functional improvement after four months of 4-AP use, though his improvement followed the expected trajectory of recovery. To date, this case represents the first case of 4-AP administration in a pediatric SCI patient, and therefore these findings contribute valuable clinical insight. By documenting the clinical trajectory of this case, this manuscript suggests 4-AP may be safe for use in pediatric patients.
Mutation of the TRIM (tripartite motif)-NHL family members brat and mei-P26 perturb the differentiation of transit-amplifying progenitor cells resulting in tumour-like phenotypes. The NHL (named ...after the NCL1, HT2A and LIN41 repeat) domain is essential for their growth suppressive activity, and they can induce cell-cycle exit in a RING-independent manner. TRIM3 is the only bona fide tumour suppressor in the mammalian TRIM-NHL subfamily and similar to the other members of this family, its ability to inhibit cell proliferation depends on the NHL domain. However, whether the RING domain was required for TRIM3-dependent cell-cycle exit had not been investigated. In the present study, we establish that the RING domain is required for TRIM3-induced growth suppression. Furthermore, we show that this domain is necessary to promote ubiquitination of p21 in a reconstituted in vitro system where UbcH5a is the preferred E2. Thus the ability of TRIM3 to suppress growth is associated with its ability to ubiquitinate proteins.
Adult patients with adrenoleukodystrophy have a poor prognosis owing to development of adrenomyeloneuropathy. Additionally, a large proportion of patients with adrenomyeloneuropathy develop ...life-threatening progressive cerebral adrenoleukodystrophy. Leriglitazone is a novel selective peroxisome proliferator-activated receptor gamma agonist that regulates expression of key genes that contribute to neuroinflammatory and neurodegenerative processes implicated in adrenoleukodystrophy disease progression. We aimed to assess the effect of leriglitazone on clinical, imaging, and biochemical markers of disease progression in adults with adrenomyeloneuropathy.
ADVANCE was a 96-week, randomised, double-blind, placebo-controlled, phase 2–3 trial done at ten hospitals in France, Germany, Hungary, Italy, the Netherlands, Spain, the UK, and the USA. Ambulatory men aged 18–65 years with adrenomyeloneuropathy without gadolinium enhancing lesions suggestive of progressive cerebral adrenoleukodystrophy were randomly assigned (2:1 without stratification) to receive daily oral suspensions of leriglitazone (150 mg starting dose; between baseline and week 12, doses were increased or decreased to achieve plasma concentrations of 200 μg·h/mL SD 20%) or placebo by means of an interactive response system and a computer-generated sequence. Investigators and patients were masked to group assignment. The primary efficacy endpoint was change from baseline in the Six-Minute Walk Test distance at week 96, analysed in the full-analysis set by means of a mixed model for repeated measures with restricted maximum likelihood and baseline value as a covariate. Adverse events were also assessed in the full-analysis set. This study was registered with ClinicalTrials.gov, NCT03231878; the primary study is complete; patients had the option to continue treatment in an open-label extension, which is ongoing.
Between Dec 8, 2017, and Oct 16, 2018, of 136 patients screened, 116 were randomly assigned; 62 81% of 77 patients receiving leriglitazone and 34 87% of 39 receiving placebo completed treatment. There was no between-group difference in the primary endpoint (mean SD change from baseline leriglitazone: –27·7 41·4 m; placebo: –30·3 60·5 m; least-squares mean difference –1·2 m; 95% CI –22·6 to 20·2; p=0·91). The most common treatment emergent adverse events in both the leriglitazone and placebo groups were weight gain (54 70% of 77 vs nine 23% of 39 patients, respectively) and peripheral oedema (49 64% of 77 vs seven 18% of 39). There were no deaths. Serious treatment-emergent adverse events occurred in 14 (18%) of 77 patients receiving leriglitazone and ten (26%) of 39 patients receiving placebo. The most common serious treatment emergent adverse event, clinically progressive cerebral adrenoleukodystrophy, occurred in six 5% of 116 patients, all of whom were in the placebo group.
The primary endpoint was not met, but leriglitazone was generally well tolerated and rates of adverse events were in line with the expected safety profile for this drug class. The finding that cerebral adrenoleukodystrophy, a life-threatening event for patients with adrenomyeloneuropathy, occurred only in patients in the placebo group supports further investigation of whether leriglitazone might slow the progression of cerebral adrenoleukodystrophy.
Minoryx Therapeutics.
How proteins participate in tumorigenesis can be obscured by their multifunctional nature. For example, depending on the cellular context, the cdk inhibitors can affect cell proliferation, cell ...motility, apoptosis, receptor tyrosine kinase signaling, and transcription. Thus, to determine how a protein contributes to tumorigenesis, we need to evaluate which functions are required in the developing tumor. Here we demonstrate that the RCAS/TvA system, originally developed to introduce oncogenes into somatic cells of mice, can be adapted to allow us to define the contribution that different functional domains make to tumor development. Studying the development of growth‐factor‐induced oligodendroglioma, we identified a critical role for the Cy elements in p21, and we showed that cyclin D1T286A, which accumulates in the nucleus of p21‐deficient cells and binds to cdk4, could bypass the requirement for p21 during tumor development. These genetic results suggest that p21 acts through the cyclin D1–cdk4 complex to support tumor growth, and establish the utility of using a somatic cell modeling system for defining the contribution proteins make to tumor development.
This case is a unique pediatric presentation of a surfer’s myelopathy, now referred to as acute hyperextension-induced myelopathy (AHIM), that provides an optimistic rehabilitation outcome. A ...13-year-old boy presented to the emergency department with back pain, paraplegia, urinary retention, and dysesthesia following his first surfing lesson while visiting Hawaii. MRI of the thoracic spine without contrast showed a significant T2 hyperintense signal in the T9-T12 distal thoracic cord, consistent with AHIM. He completed a 10-day inpatient rehabilitation program and experienced exceptional improvement in functional mobility. AHIM is a rare phenomenon that is triggered by repetitive spinal hyperextension. While there are studies describing this clinical syndrome in detail, the literature lacks information about rehabilitation outcomes for these patients. Following the diagnosis and acute management of AHIM, a comprehensive inpatient rehabilitation program is recommended to maximize functional improvement.
Phosphorylation of Tyr-88/Tyr-89 in the 310 helix of p27 reduces its cyclin-dependent kinase (CDK) inhibitory activity. This modification does not affect the interaction of p27 with cyclin-CDK ...complexes but does interfere with van der Waals and hydrogen bond contacts between p27 and amino acids in the catalytic cleft of the CDK. Thus, it had been suggested that phosphorylation of this site could switch the tumor-suppressive CDK inhibitory activity to an oncogenic activity. Here, we examined this hypothesis in the RCAS-PDGF-HA/nestin-TvA proneural glioma mouse model, in which p21 facilitates accumulation of nuclear cyclin D1-CDK4 and promotes tumor development. In these tumor cells, approximately one-third of the p21 is phosphorylated at Tyr-76 in the 310 helix. Mutation of this residue to glutamate reduced inhibitory activity in vitro. Mutation of this residue to phenylalanine reduced the tumor-promoting activity of p21 in the animal model, whereas glutamate or alanine substitution allowed tumor formation. Consequently, we conclude that tyrosine phosphorylation contributes to the conversion of CDK inhibitors from tumor-suppressive roles to oncogenic roles.
Background: Phosphorylation of Tyr in the 310 helix of p27 reduces its inhibitory activity on cyclin-CDK complexes.
Results: Mutation of this site to Phe reduces the tumor-promoting activity of p21 in the RCAS-PDGF-HA/nestin-TvA mouse model of proneural gliomagenesis.
Conclusion: Tyr phosphorylation of p21 contributes to its oncogenic role.
Significance: This mouse model establishes the significance of this modification for the nuclear accumulation of cyclin D1-CDK4.
Purpose of Review
Consciousness is a state of wakefulness with awareness of self and the environment. Disorder of consciousness (DOC) can result from any type of acquired brain injury (ABI). While ...children with ABI and DOC are commonly encountered in pediatric rehabilitation settings, research in this population is lacking, necessitating extrapolation from adult literature.
Recent Findings
Adults and children with DOC who participate in specialized inpatient rehabilitation programs show functional gains during and following the inpatient admission. Here, we present a model for an interdisciplinary rehabilitation program for children with DOC along with data supporting the evaluation and management approaches, where available.
Summary
Careful, interdisciplinary assessment using appropriate tools as well as a range of pharmacologic and non-pharmacologic interventions supports the rehabilitation and recovery of children with DOC. Additional research focused on children with DOC will be crucial for enhancing the evidence related to this population.
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