Safety of allogeneic umbilical cord blood infusions for the treatment of neurological conditions: a systematic review of clinical studies.

BACKGROUND AIMS: Umbilical cord blood (UCB) infusion is being investigated as a treatment for a range of neurological conditions, primarily because of its potent immunomodulatory effects mediated via paracrine signaling. Although initial research mainly utilized autologous UCB, allogeneic samples from a sibling or unrelated donor have now become more common. With the use of allogeneic UCB, questions have arisen surrounding the necessity for human leukocyte antigen (HLA) matching, preparative regimens and immunosuppressant drugs. To investigate the safety of allogeneic UCB for the treatment of neurological conditions and the impact of HLA mismatching and immunosuppresion, the authors conducted a systematic review of the safety of allogeneic UCB infusion for neurological conditions. METHODS: A systematic review of published and gray literature was conducted to investigate the safety of allogeneic UCB infusions for neurological conditions. RESULTS: Authors identified 10 studies using allogeneic UCB to treat autism spectrum disorder, cerebral palsy, stroke, traumatic brain injury and various other conditions. A total of 361 participants (with at least 442 UCB infusions) received a range of HLA-matched/untyped allogeneic units and cell doses, with the majority not administered post-infusion immunosuppression. There were no reported serious adverse events definitely or probably related to the allogeneic UCB infusion, nor later potential complications such as graft-versus-host disease or teratoma formation. CONCLUSIONS: Although variability between studies is high, the available data do not identify safety concerns with allogeneic UCB infusion for the treatment of neurological conditions, even with variable HLA matching or no immunosuppression.

Is the search for cerebral palsy 'cures' a reasonable and appropriate goal in the 2020s?

In the field of disability research and advocacy, the notion of 'cures' is contentious. Cerebral palsy (CP) is no exception. In this narrative review, we combine perspectives gained during community consultation undertaken for the Australian and New Zealand Cerebral Palsy Strategy, 2020 with those published in the scientific and grey literature to understand whether 'cures for CP' is a reasonable and appropriate goal. We frame these perspectives through the lens of several ethical principles central to the discussion. These include maintaining hope while also being realistic, sensitivity to sharply different viewpoints amongst people with disability and their families, and responding to community priorities, societal attitudes, and identity. Through this exploration of the literature and perspectives, we arrived at a definition of 'cures for CP' that is pluralized and focuses on functional improvement and/or symptom reduction whilst still acknowledging the potential for neural repair/regeneration strategies.

State of the Evidence Traffic Lights 2019: Systematic Review of Interventions for Preventing and Treating Children with Cerebral Palsy.

PURPOSE OF REVIEW: Cerebral palsy is the most common physical disability of childhood, but the rate is falling, and severity is lessening. We conducted a systematic overview of best available evidence (2012-2019), appraising evidence using GRADE and the Evidence Alert Traffic Light System and then aggregated the new findings with our previous 2013 findings. This article summarizes the best available evidence interventions for preventing and managing cerebral palsy in 2019. RECENT FINDINGS: Effective prevention strategies include antenatal corticosteroids, magnesium sulfate, caffeine, and neonatal hypothermia. Effective allied health interventions include acceptance and commitment therapy, action observations, bimanual training, casting, constraint-induced movement therapy, environmental enrichment, fitness training, goal-directed training, hippotherapy, home programs, literacy interventions, mobility training, oral sensorimotor, oral sensorimotor plus electrical stimulation, pressure care, stepping stones triple P, strength training, task-specific training, treadmill training, partial body weight support treadmill training, and weight-bearing. Effective medical and surgical interventions include anti-convulsants, bisphosphonates, botulinum toxin, botulinum toxin plus occupational therapy, botulinum toxin plus casting, diazepam, dentistry, hip surveillance, intrathecal baclofen, scoliosis correction, selective dorsal rhizotomy, and umbilical cord blood cell therapy. We have provided guidance about what works and what does not to inform decision-making, and highlighted areas for more research.

3D Protein Dynamics in the Cell Nucleus.

The three-dimensional (3D) architecture of the cell nucleus plays an important role in protein dynamics and in regulating gene expression. However, protein dynamics within the 3D nucleus are poorly understood. Here, we present, to our knowledge, a novel combination of 1) single-objective based light-sheet microscopy, 2) photoconvertible proteins, and 3) fluorescence correlation microscopy, to quantitatively measure 3D protein dynamics in the nucleus. We are able to acquire >3400 autocorrelation functions at multiple spatial positions within a nucleus, without significant photobleaching, allowing us to make reliable estimates of diffusion dynamics. Using this tool, we demonstrate spatial heterogeneity in Polymerase II dynamics in live U2OS cells. Further, we provide detailed measurements of human-Yes-associated protein diffusion dynamics in a human gastric cancer epithelial cell line.

Roles of RUNX in Hippo Pathway Signaling.

The Runt-domain (RD) transcription factors (RUNX genes) are an important family of transcriptional mediators that interact with a variety of proteins including the Hippo pathway effector proteins, YAP and TAZ. In this chapter we focus on two examples of RUNX-TAZ/YAP interactions that have particular significance in human cancer. Specifically, recent evidence has found that RUNX2 cooperates with TAZ to promote epithelial to mesenchymal transition mediated by the soluble N-terminal ectodomain of E-Cadherin, sE-Cad. Contrastingly, in gastric cancer, RUNX3 acts as a tumor suppressor via inhibition of the YAP-TEAD complex and disruption of downstream YAP-mediated gene transcription and the oncogenic phenotype. The reports highlighted in this chapter add to the growing repertoire of instances of Hippo pathway crosstalk that have been identified in cancer. Elucidation of these increasingly complex interactions may help to identify novel strategies to target Hippo pathway dysregulation in human cancer.

TAZ Protein Accumulation Is Negatively Regulated by YAP Abundance in Mammalian Cells.

The mammalian Hippo signaling pathway regulates cell growth and survival and is frequently dysregulated in cancer. YAP and TAZ are transcriptional coactivators that function as effectors of this signaling pathway. Aberrant YAP and TAZ activity is reported in several human cancers, and normally the expression and nuclear localization of these proteins is tightly regulated. We sought to establish whether a direct relationship exists between YAP and TAZ. Using knockdown and overexpression experiments we show YAP inversely regulates the abundance of TAZ protein by proteasomal degradation. Interestingly this phenomenon was uni-directional since TAZ expression did not affect YAP abundance. Structure/function analyses suggest that YAP-induced TAZ degradation is a consequence of YAP-targeted gene transcription involving TEAD factors. Subsequent investigation of known regulators of TAZ degradation using specific inhibitors revealed a role for heat shock protein 90 and glycogen synthase kinase 3 but not casein kinase 1 nor LATS in YAP-mediated TAZ loss. Importantly, this phenomenon is conserved from mouse to human; however, interestingly, different YAP isoforms varied in their ability to degrade TAZ. Since shRNA-mediated TAZ depletion in HeLa and D645 cells caused apoptotic cell death, we propose that isoform-specific YAP-mediated TAZ degradation may contribute to the contradicting roles reported for YAP overexpression. This study identifies a novel mechanism of TAZ regulation by YAP, which has significant implications for our understanding of Hippo pathway regulation, YAP-isoform specific signaling, and the role of these proteins in cell proliferation, apoptosis, and tumorigenesis.

Framework to function: mechanosensitive regulators of gene transcription.

Mechanobiology has shifted our understanding of fundamental cellular and physiological functions. Changes to the stiffness of the extracellular matrix, cell rigidity, or shape of the cell environment were considered in the past to be a consequence of aging or pathological processes. We now understand that these factors can actually be causative biological mediators of cell growth to control organ size. Mechanical cues are known to trigger a relatively fast translocation of specific transcriptional co-factors such as MRTFs, YAP and TAZ from the cytoplasm to the cell nucleus to initiate discrete transcriptional programs. The focus of this review is the molecular mechanisms by which biophysical stimuli that induce changes in cytoplasmic actin dynamics are communicated within cells to elicit gene-specific transcription via nuclear localisation or activation of specialized transcription factors, namely MRTFs and the Hippo pathway effectors YAP and TAZ. We propose here that MRTFs, YAP and TAZ closely collaborate as mechano-effectors.

Acceptability of neural stem cell therapy for cerebral palsy: survey of the Australian cerebral palsy community.

BACKGROUND: Neural stem cells (NSCs) have the potential to engraft and replace damaged brain tissue, repairing the damaged neonatal brain that causes cerebral palsy (CP). There are procedures that could increase engraftment of NSCs and may be critical for efficacy, but hold notable risks. Before clinical trials progress, it is important to engage with the CP community to understand their opinions. The aim of this study was to determine the acceptability of NSC therapy for CP in the CP community. METHODS: Australian residents with CP and parents/carers of those with CP completed a questionnaire to determine their willingness to use NSCs from three sources (fetal, embryonic and induced pluripotent stem cells) and their willingness to undergo accompanying procedures (neurosurgery, immunosuppression) that carry potential risks. To further explore their views, participants also answered free text questions about their ethical concerns regarding the source of NSCs and their perceptions of meaningful outcomes following NSC treatment. RESULTS: In total, 232 responses were analyzed. Participants were willing to use NSCs from all three cell sources and were willing to undergo NSC therapy despite the need for neurosurgery and immunosuppression. Participants identified a range of outcome domains considered important following NSC treatment including gross motor function, quality of life, independence and cognitive function. CONCLUSIONS: Hypothetical NSC therapy was acceptable to the Australian CP community. This study has identified important findings from the CP community which can be used to inform future NSC research, including the design of clinical trials which may help to increase recruitment, compliance and participant satisfaction.

Proportion of Infant Neurodevelopment Trials Reporting a Null Finding: A Systematic Review.

CONTEXT: Discovering new interventions to improve neurodevelopmental outcomes is a priority; however, clinical trials are challenging and methodological issues may impact the interpretation of intervention efficacy. OBJECTIVES: Characterize the proportion of infant neurodevelopment trials reporting a null finding and identify features that may contribute to a null result. DATA SOURCES: The Cochrane library, Medline, Embase, and CINAHL databases. STUDY SELECTION: Randomized controlled trials recruiting infants aged <6 months comparing any "infant-directed" intervention against standard care, placebo, or another intervention. Neurodevelopment assessed as the primary outcome between 12 months and 10 years of age using a defined list of tools. DATA EXTRACTION: Two reviewers independently extracted data and assessed quality of included studies. RESULTS: Of n = 1283 records screened, 21 studies (from 20 reports) were included. Of 18 superiority studies, >70% reported a null finding. Features were identified that may have contributed to the high proportion of null findings, including selection and timing of the primary outcome measure, anticipated effect size, sample size and power, and statistical analysis methodology and rigor. LIMITATIONS: Publication bias against null studies means the proportion of null findings is likely underestimated. Studies assessing neurodevelopment as a secondary or within a composite outcome were excluded. CONCLUSIONS: This review identified a high proportion of infant neurodevelopmental trials that produced a null finding and detected several methodological and design considerations which may have contributed. We make several recommendations for future trials, including more sophisticated approaches to trial design, outcome assessment, and analysis.

Neuroprotective Action of Tacrolimus before and after Onset of Neonatal Hypoxic-Ischaemic Brain Injury in Rats.

(1) Background: Neonatal brain injury can lead to permanent neurodevelopmental impairments. Notably, suppressing inflammatory pathways may reduce damage. To determine the role of neuroinflammation in the progression of neonatal brain injury, we investigated the effect of treating neonatal rat pups with the immunosuppressant tacrolimus at two time points: before and after hypoxic-ischaemic (HI)-induced injury. (2) Methods: To induce HI injury, postnatal day (PND) 10 rat pups underwent single carotid artery ligation followed by hypoxia (8% oxygen, 90 min). Pups received daily tacrolimus (or a vehicle) starting either 3 days before HI on PND 7 (pre-HI), or 12 h after HI (post-HI). Four doses were tested: 0.025, 0.05, 0.1 or 0.25 mg/kg/day. Pups were euthanised at PND 17 or PND 50. (3) Results: All tacrolimus doses administered pre-HI significantly reduced brain infarct size and neuronal loss, increased the number of resting microglia and reduced cellular apoptosis (p < 0.05 compared to control). In contrast, only the highest dose of tacrolimus administered post-HI (0.25 mg/kg/day) reduced brain infarct size (p < 0.05). All doses of tacrolimus reduced pup weight compared to the controls. (4) Conclusions: Tacrolimus administration 3 days pre-HI was neuroprotective, likely mediated through neuroinflammatory and cell death pathways. Tacrolimus post-HI may have limited capacity to reduce brain injury, with higher doses increasing rat pup mortality. This work highlights the benefits of targeting neuroinflammation during the acute injurious period. More specific targeting of neuroinflammation, e.g., via T-cells, warrants further investigation.

Education can improve clinician confidence in information sharing and willingness to refer to stem cell clinical trials for cerebral palsy.

To progress stem cell therapies for cerebral palsy, clinicians need to openly engage with patients about emerging evidence and be willing to refer to relevant clinical trials, if and when appropriate. To assess whether education can change clinicians' confidence in information sharing and willingness to refer to relevant clinical trials, an online questionnaire was distributed at a scientific conference before and after a professional workshop on cell therapies for cerebral palsy. Of the 42 participants who completed the survey, 26 self-identified as clinicians. Of these, 81% had had patients ask about stem cells, yet in the pre-workshop questionnaire indicated they were not confident answering questions about cell therapies. Clinicians were most commonly asked about stem cell treatments provided by private clinics, stem cell research and current evidence. Post-workshop, knowledge and confidence regarding stem cells, as well as likelihood to refer to clinical trials using therapies with a strong evidence base (eg, umbilical cord blood/placental cells), significantly increased (p<0.001). This study highlights that by offering resources and education, clinician confidence and willingness to refer to cell therapy trials can improve; this may help drive the stem cell research landscape and support patient decision-making.

Neurodevelopmental Therapy for Cerebral Palsy: A Meta-analysis.

BACKGROUND AND OBJECTIVE: Bobath therapy, or neurodevelopmental therapy (NDT) is widely practiced despite evidence other interventions are more effective in cerebral palsy (CP). The objective is to determine the efficacy of NDT in children and infants with CP or high risk of CP. METHODS: Cumulative Index to Nursing and Allied Health Literature, Cochrane Library, Embase, and Medline were searched through March 2021. Randomized controlled trials comparing NDT with any or no intervention were included. Meta-analysis was conducted with standardized mean differences calculated. Quality was assessed by using Cochrane Risk of Bias tool-2 and certainty by using Grading of Recommendations Assessment, Development, and Evaluation. RESULTS: Of 667 records screened, 34 studies (in 35 publications, 1332 participants) met inclusion. Four meta-analyses were conducted assessing motor function. We found no effect between NDT and control (pooled effect size 0.13 [-0.20 to 0.46]), a moderate effect favoring activity-based approaches (0.76 [0.12 to 1.40]) and body function and structures (0.77 [0.19 to 1.35]) over NDT and no effect between higher- and lower-dose NDT (0.32 [-0.11 to 0.75]). A strong recommendation against the use of NDT at any dose was made. Studies were not all Consolidated Standards of Reporting Trials-compliant. NDT versus activity-based comparator had considerable heterogeneity (I2 = 80%) reflecting varied measures. CONCLUSIONS: We found that activity-based and body structure and function interventions are more effective than NDT for improving motor function, NDT is no more effective than control, and higher-dose NDT is not more effective than lower-dose. Deimplementation of NDT in CP is required.

Are We Getting It Right? A Scoping Review of Outcomes Reported in Cell Therapy Clinical Studies for Cerebral Palsy.

Cell therapies are an emergent treatment for cerebral palsy (CP) with promising evidence demonstrating efficacy for improving gross motor function. However, families value improvements in a range of domains following intervention and the non-motor symptoms, comorbidities and complications of CP can potentially be targeted by cell therapies. We conducted a scoping review to describe all outcomes that have been reported in cell therapy studies for CP to date, and to examine what instruments were used to capture these. Through a systematic search we identified 54 studies comprising 2066 participants that were treated with a range of cell therapy interventions. We categorized the reported 53 unique outcome instruments and additional descriptive measures into 10 categories and 12 sub-categories. Movement and Posture was the most frequently reported outcome category, followed by Safety, however Quality of Life, and various prevalent comorbidities and complications of CP were infrequently reported. Notably, many outcome instruments used do not have evaluative properties and thus are not suitable for measuring change following intervention. We provide a number of recommendations to ensure that future trials generate high-quality outcome data that is aligned with the priorities of the CP community.

Persistent Inflammation in Cerebral Palsy: Pathogenic Mediator or Comorbidity? A Scoping Review.

Research has established inflammation in the pathogenesis of brain injury and the risk of developing cerebral palsy (CP). However, it is unclear if inflammation is solely pathogenic and primarily contributes to the acute phase of injury, or if inflammation persists with consequence in CP and may therefore be considered a comorbidity. We conducted a scoping review to identify studies that analyzed inflammatory biomarkers in CP and discuss the role of inflammation in the pathogenesis of CP and/or as a comorbidity. Twelve included studies reported a range of analytes, methods and biomarkers, including indicators of inflammatory status, immune function and genetic changes. The majority of controlled studies concluded that one or more systemic biomarkers of inflammation were significantly different in CP versus controls; most commonly serum or plasma cytokines such as tumor necrosis factor, Interleukin (IL)-6 and IL-10. In addition, differences in inflammation were noted in distinct subgroups of CP (e.g., those with varying severity). The available evidence supports the pathogenic role of inflammation and its ongoing role as a comorbidity of CP. This review shows that inflammation may persist for decades, driving functional impairment across development and into adulthood. However, inflammation is complex, thus further research will increase our understanding.

miR-582-5p Is a Tumor Suppressor microRNA Targeting the Hippo-YAP/TAZ Signaling Pathway in Non-Small Cell Lung Cancer.

The Hippo-YAP/TAZ signaling pathway is an evolutionarily conserved signaling pathway involved in a broad spectrum of biological processes, including tumorigenesis. Whilst aberrant Hippo-YAP/TAZ signaling is frequently reported in various cancers, the genetic alterations of this pathway are relatively rare, suggesting regulation at the post-transcriptional level. MicroRNAs play key role in tumorigenesis by regulating gene expression post-transcriptionally. Amongst the cancer-relevant microRNAs, miR-582-5p suppresses cell growth and tumorigenesis by inhibiting the expression of oncogenes, including AKT3, MAP3K2 and NOTCH1. Given the oncogenic role of YAP/TAZ in solid tumors, we scrutinized the possible interplay between miR-582-5p and Hippo-YAP/TAZ signaling. Correlation analysis in NSCLC cells revealed a positive relationship between the expression of mature miR-582-5p and the proportion of phosphorylated YAP/TAZ. Intriguingly, YAP/TAZ knockdown reduced the expression of mature miR-582-5p but increased that of primary miR-582. Overexpression of miR-582-5p resulted in increased phosphorylation of YAP/TAZ with a concomitant reduction in cell proliferation and enhanced apoptosis. Mechanistically, we find that miR-582-5p targets actin regulators NCKAP1 and PIP5K1C, which may be responsible for the observed alteration in F-actin, known to modulate YAP/TAZ. We postulate that regulation of the actin cytoskeleton by miR-582-5p may attenuate YAP/TAZ activity. Altogether, this study reveals a novel mechanism of YAP/TAZ regulation by miR-582-5p in a cytoskeleton-dependent manner and suggests a negative feedback loop, highlighting the therapeutic potential of restoring miR-582-5p expression in treating NSCLC.

Rehabilitation Evidence-Based Decision-Making: The READ Model.

Evidence-based practice is the foundation of rehabilitation for maximizing client outcomes. However, an unacceptably high number of ineffective or outdated interventions are still implemented, leading to sub-optimal outcomes for clients. This paper proposes the Rehabilitation Evidence bAsed Decision-Making (READ) Model, a decision-making algorithm for evidence-based decision-making in rehabilitation settings. The READ Model outlines a step-by-step layered process for healthcare professionals to collaboratively set goals, and to select appropriate interventions. The READ Model acknowledges the important multi-layered contributions of client's preferences and values, family supports available, and external environmental factors such as funding, availability of services and access. Healthcare professionals can apply the READ Model to choose interventions that are evidence-based, with an appropriate mode, dose, and with regular review, in order to achieve client's goals. Two case studies are used to demonstrate application of the READ Model: cerebral palsy and autism spectrum disorder. The READ Model applies the four central principles of evidence-based practice and can be applied across multiple rehabilitation settings.

Neural stem cell treatment for perinatal brain injury: A systematic review and meta-analysis of preclinical studies.

Perinatal brain injury can lead to significant neurological and cognitive deficits and currently no therapies can regenerate the damaged brain. Neural stem cells (NSCs) have the potential to engraft and regenerate damaged brain tissue. The aim of this systematic review was to evaluate the preclinical literature to determine whether NSC administration is more effective than controls in decreasing perinatal brain injury. Controlled interventional studies of NSC therapy using animal models of perinatal brain injury were identified using MEDLINE and Embase. Primary outcomes were brain infarct size, motor, and cognitive function. Data for meta-analysis were synthesized and expressed as standardized mean difference (SMD) with 95% confidence intervals (CI), using a random effects model. We also reported secondary outcomes including NSC survival, migration, differentiation, and effect on neuroinflammation. Eighteen studies met inclusion criteria. NSC administration decreased infarct size (SMD 1.09; CI: 0.44, 1.74, P = .001; I2  = 74%) improved motor function measured via the impaired forelimb preference test (SMD 2.27; CI: 0.85, 3.69, P = .002; I2  = 86%) and the rotarod test (SMD 1.88; CI: 0.09, 3.67, P = .04; I2  = 95%). Additionally, NSCs improved cognitive function measured via the Morris water maze test (SMD of 2.41; CI: 1.16, 3.66, P = .0002; I2  = 81%). Preclinical evidence suggests that NSC therapy is promising for the treatment of perinatal brain injury. We have identified key knowledge gaps, including the lack of large animal studies and uncertainty regarding the necessity of immunosuppression for NSC transplantation in neonates. These knowledge gaps should be addressed before NSC treatment can effectively progress to clinical trial.

Positive perception of stem cells for neurological conditions: results from an Australian public forum.

Background: Stem cells offer great hope and promise as a potential treatment for human diseases. The aim of this study was to gain insight into the public perception of stem cells for neurological conditions. Materials & methods: A paper-based questionnaire was administered to all attendees of a free, public stem cell forum. Results: Of 203 respondents, >95% believe that stem cells have the potential to treat neurological conditions. There was also high support (92%) for the use of embryonic/fetally derived cells, and 67% of respondents indicated a high likelihood to participate in a clinical trial of stem cell treatment(s), indicating overall support for research and translation. Conclusion: Our data demonstrates a positive perception of stem cell treatments for neurological conditions in our cohort.