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Pre-clinical trials have demonstrated the neuroprotective effects of transplanted human neural stem cells (hNSCs) during the post-ischemic phase. However, the exact neuroprotective mechanism remains unclear. Tunneling nanotubes (TNTs) are long plasma membrane bridges that physically connect distant cells, enabling the intercellular transfer of mitochondria and contributing to post-ischemic repair processes. Whether hNSCs communicate through TNTs and their role in post-ischemic neuroprotection remains unknown. In this study, non-immortalized hNSC lines derived from fetal human brain tissues were examined to explore these possibilities and assess the post-ischemic neuroprotection potential of these hNSCs. Using Tau-STED super-resolution confocal microscopy, live cell time-lapse fluorescence microscopy, electron microscopy, and direct or non-contact homotypic co-cultures, we demonstrated that hNSCs generate nestin-positive TNTs in both 3D neurospheres and 2D cultures, through which they transfer functional mitochondria. Co-culturing hNSCs with differentiated SH-SY5Y ( d SH-SY5Y) revealed heterotypic TNTs allowing mitochondrial transfer from hNSCs to d SH-SY5Y. To investigate the role of heterotypic TNTs in post-ischemic neuroprotection, d SH-SY5Y were subjected to oxygen-glucose deprivation (OGD) followed by reoxygenation (OGD/R) with or without hNSCs in direct or non-contact co-cultures. Compared to normoxia, OGD/R d SH-SY5Y became apoptotic with impaired electrical activity. When OGD/R d SH-SY5Y were co-cultured in direct contact with hNSCs, heterotypic TNTs enabled the transfer of functional mitochondria from hNSCs to OGD/R d SH-SY5Y, rescuing them from apoptosis and restoring the bioelectrical profile toward normoxic d SH-SY5Y. This complete neuroprotection did not occur in the non-contact co-culture. In summary, our data reveal the presence of a functional TNTs network containing nestin within hNSCs, demonstrate the involvement of TNTs in post-ischemic neuroprotection mediated by hNSCs, and highlight the strong efficacy of our hNSC lines in post-ischemic neuroprotection. Human neural stem cells (hNSCs) communicate with each other and rescue ischemic neurons through nestin-positive tunneling nanotubes (TNTs). A Functional mitochondria are exchanged via TNTs between hNSCs. B hNSCs transfer functional mitochondria to ischemic neurons through TNTs, rescuing neurons from ischemia/reperfusion ROS-dependent apoptosis.

Tunneling nanotubes (TNTs) are long F-actin-positive plasma membrane bridges connecting distant cells, allowing the intercellular transfer of cellular cargoes, and are found to be involved in glioblastoma (GBM) intercellular crosstalk. Glial fibrillary acid protein (GFAP) is a key intermediate filament protein of glial cells involved in cytoskeleton remodeling and linked to GBM progression. Whether GFAP plays a role in TNT structure and function in GBM is unknown. Here, analyzing F-actin and GFAP localization by laser-scan confocal microscopy followed by 3D reconstruction (3D-LSCM) and mitochondria dynamic by live-cell time-lapse fluorescence microscopy, we show the presence of GFAP in TNTs containing functional mitochondria connecting distant human GBM cells. Taking advantage of super-resolution 3D-LSCM, we show the presence of GFAP-positive TNT-like structures in resected human GBM as well. Using H 2 O 2 or the pro-apoptotic toxin staurosporine (STS), we show that GFAP-positive TNTs strongly increase during oxidative stress and apoptosis in the GBM cell line. Culturing GBM cells with STS-treated GBM cells, we show that STS triggers the formation of GFAP-positive TNTs between them. Finally, we provide evidence that mitochondria co-localize with GFAP at the tip of close-ended GFAP-positive TNTs and inside receiving STS-GBM cells. Summarizing, here we found that GFAP is a structural component of TNTs generated by GBM cells, that GFAP-positive TNTs are upregulated in response to oxidative stress and pro-apoptotic stress, and that GFAP interacts with mitochondria during the intercellular transfer. These findings contribute to elucidate the molecular structure of TNTs generated by GBM cells, highlighting the structural role of GFAP in TNTs and suggesting a functional role of this intermediate filament component in the intercellular mitochondria transfer between GBM cells in response to pro-apoptotic stimuli.

Anxiety and depression in cardiac rehabilitation (CR) are associated with greater morbidity, mortality, and increased healthcare costs. Current psychological interventions within CR have small effects based on low-quality studies of clinic-based interventions with limited access to home-based psychological support. We tested the effectiveness of adding self-help metacognitive therapy (Home-MCT) to CR in reducing anxiety and depression in a randomised controlled trial (RCT). We ran a single-blind, multi-centre, two-arm RCT. A total of 240 CR patients were recruited from 5 NHS-Trusts across North West England between April 20, 2017 and April 6, 2020. Patients were randomly allocated to Home-MCT+CR (n = 118, 49.2%) or usual CR alone (n = 122, 50.8%). Randomisation was 1:1 via randomised blocks within hospital site, balancing arms on sex and baseline Hospital Anxiety and Depression Scale (HADS) scores. The primary outcome was the HADS total score at posttreatment (4-month follow-up). Follow-up data collection occurred between August 7, 2017 and July 20, 2020. Analysis was by intention to treat. The 4-month outcome favoured the MCT intervention group demonstrating significantly lower end of treatment scores (HADS total: adjusted mean difference = -2.64 [-4.49 to -0.78], p = 0.005, standardised mean difference (SMD) = 0.38). Sensitivity analysis using multiple imputation (MI) of missing values supported these findings. Most secondary outcomes also favoured Home-MCT+CR, especially in reduction of post-traumatic stress symptoms (SMD = 0.51). There were 23 participants (19%) lost to follow-up in Home-MCT+CR and 4 participants (3%) lost to follow-up in CR alone. No serious adverse events were reported. The main limitation is the absence of longer term (e.g., 12-month) follow-up data. Self-help home-based MCT was effective in reducing total anxiety/depression in patients undergoing CR. Improvement occurred across most psychological measures. Home-MCT was a promising addition to cardiac rehabilitation and may offer improved access to effective psychological treatment in cardiovascular disease (CVD) patients. NCT03999359.

This study evaluated the phytoextraction capacity of the fern Pteris vittata grown on a natural arsenic-rich soil of volcanic-origin from the Viterbo area in central Italy. This calcareous soil is characterized by an average arsenic concentration of 750 mg kg −1 , of which 28% is bioavailable. By means of micro-energy dispersive X-ray fluorescence spectrometry (μ-XRF) we detected As in P. vittata fronds after just 10 days of growth, while a high As concentrations in fronds (5,000 mg kg −1 ), determined by Inductively coupled plasma-optical emission spectrometry (ICP-OES), was reached after 5.5 months. Sixteen arsenate-tolerant bacterial strains were isolated from the P. vittata rhizosphere, a majority of which belong to the Bacillus genus, and of this majority only two have been previously associated with As . Six bacterial isolates were highly As-resistant (> 100 mM) two of which, homologous to Paenarthrobacter ureafaciens and Beijerinckia fluminensis, produced a high amount of IAA and siderophores and have never been isolated from P. vittata roots. Furthermore, five isolates contained the arsenate reductase gene ( ars C). We conclude that P. vittata can efficiently phytoextract As when grown on this natural As-rich soil and a consortium of bacteria, largely different from that usually found in As-polluted soils, has been found in P. vittata rhizosphere.

Rituximab (RTX) efficacy in NMO is suggested by several case series. No consensus exists on optimal dosing strategies. At present the treatment schedules more frequently used are 375 mg/m2/week iv for 4 weeks (RTX-A) and 1000 mg iv twice, 2 weeks apart (RTX-B). Aim of this study is to confirm RTX efficacy and safety in the treatment of NMO and to evaluate whether a most favourable dosage regimen exists. Data on RTX-treated NMO patients were collected from 13 Italian Hospitals. 73 patients (64 F), were enlisted. RTX-A was administered in 42/73 patients, RTX-B in 31/73. Median follow-up was 27 months (range 7–106). Mean relapse rate in the previous year before RTX start was 2.2 ± 1.3 for RTX-A and 2.3 ± 1.2 for RTX-B. ARR in the first year of treatment was 0.8 ± 0.9 for RTX-A and 0.2 ± 0.4 for RTX-B, in the second year of treatment was 0.9 ± 1.5 for RTX-A and 0.4 ± 0.8 for RTX-B patients ( p  = 0.001 for the first year, ns (0.09) for the second year). RTX-B was more effective in delaying the occurrence of a relapse (HR 2.2 (95 % IC 1.08–4.53) p  = 0.02). Adverse events were described in 19/73 patients (mainly urinary tract and respiratory infections, and infusion reactions). Two deaths were reported in severely disabled patients. Though with the limitations of an observational study, our data support RTX efficacy in NMO and suggest that high dose pulses might be more effective than a more fractioned dose.

Objective: Reoperations for spinopelvic failure after adult spinal deformity (ASD) surgery are common. We sought to determine the added costs of ASD surgery attributable to reoperations for spinopelvic construct failures. Methods: We constructed a Markov process model to calculate the expected discounted 5-year costs of spinopelvic construct failures after ASD surgery. The Nationwide Inpatient Sample (NIS) was queried to estimate the number of ASD surgeries. Model inputs were based on literature review and expert opinion. ASD surgery was defined as thoracolumbar fusion of 4 or more levels with pelvic fixation. The following pelvic fixation failures were included: 1) rod fracture or pseudarthrosis from L4-S1, 2) iliac screw failure or set plug dislodgment, 3) iliac screw prominence, and 4) sacroiliac (SI) joint pain. The number of patients undergoing ASD surgery annually in the US was determined using a commercial claims database. Results: The net present value 5-year cost per patient for spinopelvic complications was $35,265, equal to 29% of index surgery costs. Given an estimated 27,580 cases annually in the US, the additional cost to address spinopelvic complications reach nearly $1 billion over 5-years. A sensitivity analysis showed that these costs were most sensitive to the rate of rod fracture/pseudarthrosis, iliac screw prominence, and reoperation. Conclusion: A conservative estimate of the cost of spinopelvic failures after ASD surgery is substantial, nearly $1 billion over 5-years. We propose a method of capturing spinopelvic fixation failures for use in future clinical studies and cost analyses. Keywords: spinopelvic, sacroiliac, deformity surgery

Considerable interest has been generated from the results of recent clinical trials using smoothened (SMO) antagonists to inhibit the growth of hedgehog (HH) signaling-dependent tumors. This interest is tempered by the discovery of SMO mutations mediating resistance, underscoring the rationale for developing therapeutic strategies that interrupt HH signaling at levels distinct from those inhibiting SMO function. Here, we demonstrate that HH-dependent non-small cell lung carcinoma (NSCLC) growth is sensitive to blockade of the HH pathway upstream of SMO, at the level of HH ligand processing. Individually, the use of different lentivirally delivered shRNA constructs targeting two functionally distinct HH-processing proteins, skinny hedgehog (SKN) or dispatched-1 (DISP-1), in NSCLC cell lines produced similar decreases in cell proliferation and increased cell death. Further, providing either an exogenous source of processed HH or a SMO agonist reverses these effects. The attenuation of HH processing, by knocking down either of these gene products, also abrogated tumor growth in mouse xenografts. Finally, we extended these findings to primary clinical specimens, showing that SKN is frequently overexpressed in NSCLC and that higher DISP-1 expression is associated with an unfavorable clinical outcome. Our results show a critical role for HH processing in HH-dependent tumors, identifies two potential druggable targets in the HH pathway, and suggest that similar therapeutic strategies could be explored to treat patients harboring HH ligand-dependent cancers.

The association between inflammatory dysregulation and cervical carcinogenesis and progression has not yet been fully elucidated. We aimed to comprehensively evaluate the genetic association between inflammation and cervical cancer, and construct an accurate prognosis model based on circulating inflammatory parameters and indexes with machine learning (ML) algorithms. We tested the genome-wide association of circulating inflammatory molecules (CIMs) (91 circulating inflammatory cytokines and 10 inflammatory cells) and summary data retrieved from the UK biobank (cases = 1659 and controls =381,902) with two-sample Mendelian randomization (MR) and colocalization analyses. Nine ML and logistic regression (LR) integrated prognosis models were developed for 1042 subjects with cervical cancer (random allocation into training and validation cohorts at 6:4 ratio). Three potential causative CIMs for cervical cancer were identified via a two-sample MR. However, neither reverse MR, nor Bayesian colocalization analyses supported shared causal variation. After feature selection with 3 algorithms (LASSO regression, Boruta and Support vector machines), the gradient boosting machine (GBM) model outperformed other models by achieving an area under the curve (AUC) of 0.930 and a Brier score of 0.027 in 1-year overall survival (OS) prediction. Similarly, the GBM model delivered the best overall performance in 5-year OS prediction with an AUC of 0.893 and a Brier score of 0.089. Following the Shapley Additive explanations (SHAP), the lymphocyte monocyte ratio, neutrophil count, platelet count, and platelet lymphocyte ratio were associated with 1-year OS, while the systemic immune-inflammation index, platelet neutrophil ratio, and monocyte count were significantly related to 5-year OS. No substantial causal associations were observed between CIMs and cervical cancer. The cohort study findings reveal the persistent impact of inflammation on cervical cancer prognosis, highlighting the crucial role of chronic inflammation when investigating the biomarkers of cervical cancer progression and developing pharmacological interventions. The GBM model consistently achieved satisfactory performance in cervical cancer prognosis prediction with demographics and CIMs, meriting further validation and potential clinical implementation.

ObjectivesThe burden of cardiovascular disease (CVD) is increasing. Cardiac rehabilitation (CR) is a complex intervention offered to patients with CVD, following a heart event, diagnosis or intervention, and it aims to reduce mortality and morbidity. The objective of this within-trial economic evaluation was to compare the cost-effectiveness of metacognitive therapy (MCT) plus usual care (UC) to UC, from a health and social care perspective in the UK.MethodsA multicentre, single-blind, randomised controlled trial (ISRCTN74643496) was conducted in the UK involving 332 patients with CR with elevated symptoms of anxiety and/or depression and compared group-based MCT with UC. The primary outcome of the cost-effectiveness analysis was quality-adjusted life-years (QALYs). The time horizon of the primary analysis was a 12-month follow-up. Missing data were imputed using multiple imputation. Uncertainty was explored by probabilistic bootstrapping. Sensitivity analyses tested the impact of the study design and assumptions on the incremental cost-effectiveness ratio.ResultsIn the primary cost-effectiveness analysis, MCT intervention was dominant, with a cost-saving (net cost −£219; 95% CI −£1446, £1007) and QALY gains (net QALY 0.015; 95% CI −0.015, 0.045). However, there is a high level of uncertainty in the estimates. At a threshold of £30 000 per QALY, MCT intervention of around 76% was likely to be cost-effective.ConclusionsResults suggest that intervention may be cost-saving and health-increasing; however, findings are uncertain and subject to limitations. Further research should aim to reduce the uncertainty in the findings (eg, with larger sample sizes) and explore potential longer-term economic benefits associated with MCT in this setting.

The SMOOTHENED inhibitor vismodegib is FDA approved for advanced basal cell carcinoma (BCC), and shows promise in clinical trials for SONIC HEDGEHOG (SHH)-subgroup medulloblastoma (MB) patients. Clinical experience with BCC patients shows that continuous exposure to vismodegib is necessary to prevent tumor recurrence, suggesting the existence of a vismodegib-resistant reservoir of tumor-propagating cells. We isolated such tumor-propagating cells from a mouse model of SHH-subgroup MB and grew them as sphere cultures. These cultures were enriched for the MB progenitor marker SOX2 and formed tumors in vivo . Moreover, while their ability to self-renew was resistant to SHH inhibitors, as has been previously suggested, this self-renewal was instead WNT-dependent. We show here that loss of Trp53 activates canonical WNT signaling in these SOX2-enriched cultures. Importantly, a small molecule WNT inhibitor was able to reduce the propagation and growth of SHH-subgroup MB in vivo , in an on-target manner, leading to increased survival. Our results imply that the tumor-propagating cells driving the growth of bulk SHH-dependent MB are themselves WNT dependent. Further, our data suggest combination therapy with WNT and SHH inhibitors as a therapeutic strategy in patients with SHH-subgroup MB, in order to decrease the tumor recurrence commonly observed in patients treated with vismodegib.