Glioblastoma (GBM) is characterized by aberrant vascularization and a complex tumor microenvironment. The failure of anti-angiogenic therapies suggests pathways of GBM neovascularization, possibly ...attributable to glioblastoma stem cells (GSCs) and their interplay with the tumor microenvironment. It has been established that GSC-derived extracellular vesicles (GSC-EVs) and their cargoes are proangiogenic in vitro. To further elucidate EV-mediated mechanisms of neovascularization in vitro, we perform RNA-seq and DNA methylation profiling of human brain endothelial cells exposed to GSC-EVs. To correlate these results to tumors in vivo, we perform histoepigenetic analysis of GBM molecular profiles in the TCGA collection. Remarkably, GSC-EVs and normal vascular growth factors stimulate highly distinct gene regulatory responses that converge on angiogenesis. The response to GSC-EVs shows a footprint of post-transcriptional gene silencing by EV-derived miRNAs. Our results provide insights into targetable angiogenesis pathways in GBM and miRNA candidates for liquid biopsy biomarkers.
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•GBM EVs and growth factors promote angiogenesis by distinct pathways•EV-exposed endothelial cells show a footprint of gene regulation by EV miRNAs•The EV miRNA pathway explains failure of anti-angiogenic therapy for GBM•The results suggest an angiogenic pathway and liquid biopsy biomarkers for GBM
Extensive intercellular interactions occur within the notoriously heterogeneous tumor microenvironment of GBM. Lucero et al. identify distinct angiogenic gene regulatory responses of brain endothelial cells to growth factors and to extracellular vesicles (EVs) secreted by GBM stem-like cells. The response to EVs shows a footprint of EV-derived miRNAs.
Spinal cord compression caused by spinal tumors is measured using the epidural spinal cord compression scale, also known as the Bilsky score. Whether Bilsky score predicts short-/long-term outcomes ...remains unknown. The objectives were to determine the correlation of Bilsky score 0-1 vs 2-3 with regards to (1) preoperative presentation, (2) perioperative variables, and (3) long-term outcomes.
A single-center, retrospective evaluation of a cohort of patients undergoing metastatic spine surgery was performed between 01/2010 and 01/2021. Multivariable logistic/linear/Cox regression were performed controlling for age, body mass index, race, total decompressed levels, tumor size, other organ metastases, and postoperative radiotherapy/chemotherapy.
Of 343 patients with extradural spinal metastasis, 92 (26.8%) were Bilsky 0-1 and 251 (73.2%) were Bilsky 2-3. Preoperatively, patients with Bilsky 2-3 lesions were older ( P = .008), presented more with sensory deficits ( P = .029), and had worse preoperative Karnofsky Performance Scale (KPS) ( P = .002). Perioperatively, Bilsky 2-3 patients had more decompressed levels ( P = .005) and transpedicular decompression ( P < .001), with similar operative time ( P = .071) and blood loss ( P = .502). Although not statistically significant, patients with Bilsky 2-3 had more intraoperative neuromonitoring changes ( P = .412). Although rates of complications ( P = .442) and neurological deficit ( P = .852) were similar between groups, patients with Bilsky 2-3 lesions had a longer length of stay ( P = .007) and were discharged home less frequently ( P < .001). No difference was found in 90-day readmissions ( P = .607) and reoperation ( P = .510) Long-term: LR ( P =.100) and time to LR (log-rank; P =0.532) were not significantly different between Bilsky 0-1 and Bilsky 2-3 lesions. However, patients with Bilsky 2-3 lesions had worse postoperative KPS ( P < .001), worse modified McCormick scale score ( P = .003), shorter overall survival (OS) (log-rank; P < .001), and worse survival at 1 year ( P = .012). Bilsky 2-3 lesions were associated with shorter OS on multivariable Cox regression (hazard ratio = 1.78, 95% CI = 1.27-2.49, P < .001), with no significant impact on time to LR (hazard ratio = 0.73, 95% CI = 0.37-1.44, P = .359).
Bilsky 2-3 lesions were associated with longer length of stay, more nonhome discharge, worse postoperative KPS/modified McCormick scale score, shorter OS, and reduced survival at 1 year. Higher-grade Bilsky score lesions appear to be at a higher risk for worse outcomes. Efforts should be made to identify metastatic spine patients before they reach the point of severe spinal cord compression..
Sequencing has revealed hundreds of millions of human genetic variants, and continued efforts will only add to this variant avalanche. Insufficient information exists to interpret the effects of most ...variants, limiting opportunities for precision medicine and comprehension of genome function. A solution lies in experimental assessment of the functional effect of variants, which can reveal their biological and clinical impact. However, variant effect assays have generally been undertaken reactively for individual variants only after and, in most cases long after, their first observation. Now, multiplexed assays of variant effect can characterise massive numbers of variants simultaneously, yielding variant effect maps that reveal the function of every possible single nucleotide change in a gene or regulatory element. Generating maps for every protein encoding gene and regulatory element in the human genome would create an 'Atlas' of variant effect maps and transform our understanding of genetics and usher in a new era of nucleotide-resolution functional knowledge of the genome. An Atlas would reveal the fundamental biology of the human genome, inform human evolution, empower the development and use of therapeutics and maximize the utility of genomics for diagnosing and treating disease. The Atlas of Variant Effects Alliance is an international collaborative group comprising hundreds of researchers, technologists and clinicians dedicated to realising an Atlas of Variant Effects to help deliver on the promise of genomics.
The authors report a nonsimultaneous chain of 10 kidney transplantations, which was initiated in July 2007 by a single altruistic donor and involved six transplantation centers in five states. This ...strategy, coordinated by two large, paired-donation registries with the use of powerful computer programs, can potentially result in more kidney transplantations.
The authors report a nonsimultaneous chain of 10 kidney transplantations, which was initiated in July 2007 by a single altruistic donor and involved six transplantation centers in five states. This strategy can potentially result in more kidney transplantations.
Paired kidney donation is an evolving strategy for overcoming the barriers that confront patients with end-stage renal disease when the only living potential donors who are willing to donate to them are deemed to be unsuitable as donors for them owing to an incompatibility of blood type, of HLA crossmatch, or of both. In the most basic form of paired donation, the incompatibility problems with two donor–recipient pairs can be solved by exchanging donors.
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Using advanced software, several organizations have arranged paired kidney donations involving three or more pairs.
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,
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Recent reports describe simultaneously performed “domino transplantations” initiated by . . .
Extracellular vesicles (EVs), membrane-bound particles containing a variety of RNA types, DNA, proteins, and other macromolecules, are now appreciated as an important means of communication between ...cells and tissues, both in normal cellular physiology and as a potential indicator of cellular stress, environmental exposures, and early disease pathogenesis. Extracellular signaling through EVs is a growing field of research for understanding fundamental mechanisms of health and disease and for the potential for biomarker discovery and therapy development. EVs are also known to play important roles in mediating the effects of exposure to environmental stress.
This seminar addresses the application of new tools and approaches for EV research, developed in part through the National Institutes of Health (NIH) Extracellular RNA Communication Program, and reflects presentations and discussions from a workshop held 27-28 September 2021 by the National Institute of Environmental Health Sciences (NIEHS) and the National Center for Advancing Translational Sciences (NCATS) on "Extracellular Vesicles, Exosomes, and Cell-Cell Signaling in Response to Environmental Stress." The panel of experts discussed current research on EVs and environmental exposures, highlighted recent advances in EV isolation and characterization, and considered research gaps and opportunities toward identifying and characterizing the roles for EVs in environmentally related diseases, as well as the current challenges and opportunities in this field.
The authors discuss the application of new experimental models, particularly organ-on-chip (OOC) systems and
approaches and how these have the potential to extend findings in population-based studies of EVs in exposure-related diseases. Given the complex challenges of identifying cell-specific EVs related to environmental exposures, as well as the general heterogeneity and variability in EVs in blood and other accessible biological samples, there is a critical need for rigorous reporting of experimental methods and validation studies. The authors note that these efforts, combined with cross-disciplinary approaches, would ensure that future research efforts in environmental health studies on EV biomarkers are rigorous and reproducible. https://doi.org/10.1289/EHP12980.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Retrospective case-control study.
In a cohort of patients undergoing metastatic spine surgery, we sought to: (1) identify risk factors associated with unplanned readmission, and (2) determine the ...impact of an unplanned readmission on long-term outcomes.
Factors affecting readmission after metastatic spine surgery remain relatively unexplored.
A single-center, retrospective, case-control study was undertaken of patients undergoing spine surgery for extradural metastatic disease between 02/2010 and 01/2021. The primary outcome was 3-month unplanned readmission. Preoperative, perioperative, and tumor-specific variables were collected. Multivariable Cox regression was performed, controlling for tumor size, other organ metastasis, and preoperative/postoperative radiotherapy/chemotherapy.
A total of 357 patients underwent surgery for spinal metastases with a mean follow-up of 538.7±648.6 days. Unplanned readmission within 3 months of surgery occurred in 64/357 (21.9%) patients, 37 (57.8%) were medical, 27 (42.2%) surgical, and 21 (77.7%) were related to their spine surgery. No significant differences were found regarding demographics and preoperative variables, except for insurance, where most readmitted patients had private insurance compared with nonreadmitted patients ( P =0.021). No significant difference was found in preoperative radiotherapy/chemotherapy. Regarding perioperative exposure variables, readmitted patients had a higher rate of postoperative complications (68.8% vs. 24.2%, P <0.001) and worse postoperative Karnofsky Performance Score ( P =0.021) and Modified McCormick Scale ( P =0.015) at the time of first follow-up. On multivariate logistic regression, postoperative complications were associated with increased readmissions (odds ratio=1.38, 95% CI=1.25-1.52, P <0.001). Regarding the impact of unplanned readmission on long-term tumor control, unplanned readmission was associated with shorter time to local recurrence (log-rank; P =0.029) and reduced overall survival (OS) (log-rank; P <0.001). On multivariate Cox regression, other organ metastasis hazard ratio (HR)=1.48, 95% CI=1.13-1.93, P =0.004 and 3-month readmission (HR=1.75, 95% CI=1.28-2.39, P <0.001) were associated with worsened OS, with no impact on LR. Postoperative chemotherapy was significantly associated with longer OS (HR=0.59, 95% CI=0.45-0.77, P <0.001).
Postoperative complications were associated with unplanned readmission following metastatic spine surgery. Furthermore, 3-month unplanned readmission was associated with a shorter time to local recurrence and decreased OS. These results help surgeons understand the drivers of readmissions and the impact of readmissions on patient outcomes.
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Individuals with autism spectrum disorders (ASD) may be disproportionately at risk of experiencing sexual abuse and victimization. Moreover, limited research suggests some individuals with ASD may be ...more likely to engage in sexual offending behavior. The present review addresses both sexual abuse and offending within the ASD population. The literature review was conducted utilizing PsycINFO and the Education Resources Information Center. Characteristics of the ASD population and how they relate to both victimization and offending are assessed. Additionally, a brief review of sexual education for this population is presented.
Purpose
(1) Evaluate the associations between L1-pelvic angle (L1PA) and both sagittal vertical axis (SVA) and T1-pelvic angle (T1PA), and (2) assess the clinical impact of L1PA.
Methods
A ...single-institution retrospective cohort study was undertaken for patients undergoing adult spinal deformity (ASD) surgery from 2013 to 2017. Ideal L1PA was defined as (0.5xPelvic Incidence)-21. Pearson correlation was performed to compare L1PA, SVA, and T1PA. Univariate/multivariate regression was performed to assess the effect of L1PA on mechanical complications, controlling for age, BMI, and postoperative pelvic incidence-lumbar lordosis mismatch (PI/LL). Due to the overlapping nature of patients with pseudarthrosis and rod fracture, these patients were analyzed together.
Results
A total of 145 patients were included. Mean preoperative L1PA, SVA, and T1PA were 15.5 ± 8.9°, 90.7 ± 66.8 mm, and 27.1 ± 13.0°, respectively. Mean postoperative L1PA, SVA, and T1PA were 15.0 ± 8.9°, 66.7 ± 52.8 mm, and 22.3 ± 11.1°, respectively. Thirty-six (24.8%) patients achieved ideal L1PA. Though the correlation was modest, preoperative L1PA was linearly correlated with preoperative SVA (
r
2
= 0.16,
r
= 0.40, 95%CI = 0.22–0.60,
p
< 0.001) and T1PA (
r
2
= 0.41,
r
= 0.62, 95%CI = 0.46–0.76,
p
< 0.001). Postoperative L1PA was linearly correlated with postoperative SVA (
r
2
= 0.12,
r
= 0.37, 95%CI = 0.18–0.56,
p
< 0.001) and T1PA (
r
2
= 0.40,
r
= 0.62, 95%CI = 0.45–0.74,
p
< 0.001). Achieving ideal L1PA ± 5° was associated with a decreased risk of rod fracture/pseudarthrosis on univariate and multivariate regression (OR = 0.33, 95%CI = 0.12–0.86,
p
= 0.024). No association between achieving ideal L1PA and patient-reported outcomes was observed.
Conclusion
L1PA was modestly correlated with SVA and T1PA, and achieving ideal L1PA was associated with lower rates of rod fracture/pseudarthrosis. Future studies are warranted to better define the clinical implications of achieving a normal L1PA.
Level of evidence
III.
Bile acids repress the transcription of cytochrome P450 7A1 (CYP7A1), which catalyzes the rate-limiting step in bile acid biosynthesis. Although bile acids activate the farnesoid X receptor (FXR), ...the mechanism underlying bile acid–mediated repression of
CYP7A1 remained unclear. We have used a potent, nonsteroidal FXR ligand to show that FXR induces expression of small heterodimer partner 1 (SHP-1), an atypical member of the nuclear receptor family that lacks a DNA-binding domain. SHP-1 represses expression of
CYP7A1 by inhibiting the activity of liver receptor homolog 1 (LRH-1), an orphan nuclear receptor that is known to regulate
CYP7A1 expression positively. This bile acid–activated regulatory cascade provides a molecular basis for the coordinate suppression of
CYP7A1 and other genes involved in bile acid biosynthesis.
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