Arterial hemodynamic shear stress and blood vessel stiffening both significantly influence the arterial endothelial cell (EC) phenotype and atherosclerosis progression, and both have been shown to ...signal through cell-matrix adhesions. However, the cooperative effects of fluid shear stress and matrix stiffness on ECs remain unknown. To investigate these cooperative effects, we cultured bovine aortic ECs on hydrogels matching the elasticity of the intima of compliant, young, or stiff, aging arteries. The cells were then exposed to laminar fluid shear stress of 12 dyn/cm2. Cells grown on more compliant matrices displayed increased elongation and tighter EC-cell junctions. Notably, cells cultured on more compliant substrates also showed decreased RhoA activation under laminar shear stress. Additionally, endothelial nitric oxide synthase and extracellular signal-regulated kinase phosphorylation in response to fluid shear stress occurred more rapidly in ECs cultured on more compliant substrates, and nitric oxide production was enhanced. Together, our results demonstrate that a signaling cross talk between stiffness and fluid shear stress exists within the vascular microenvironment, and, importantly, matrices mimicking young and healthy blood vessels can promote and augment the atheroprotective signals induced by fluid shear stress. These data suggest that targeting intimal stiffening and/or the EC response to intima stiffening clinically may improve vascular health.
Amyotrophic lateral sclerosis (ALS) is a devastating and universally fatal neurodegenerative disease. Mutations in two related RNA-binding proteins, TDP-43 and FUS, that harbor prion-like domains, ...cause some forms of ALS. There are at least 213 human proteins harboring RNA recognition motifs, including FUS and TDP-43, raising the possibility that additional RNA-binding proteins might contribute to ALS pathogenesis. We performed a systematic survey of these proteins to find additional candidates similar to TDP-43 and FUS, followed by bioinformatics to predict prion-like domains in a subset of them. We sequenced one of these genes, TAF15, in patients with ALS and identified missense variants, which were absent in a large number of healthy controls. These disease-associated variants of TAF15 caused formation of cytoplasmic foci when expressed in primary cultures of spinal cord neurons. Very similar to TDP-43 and FUS, TAF15 aggregated in vitro and conferred neurodegeneration in Drosophila, with the ALS-linked variants having a more severe effect than wild type. Immunohistochemistry of postmortem spinal cord tissue revealed mislocalization of TAF15 in motor neurons of patients with ALS. We propose that aggregation-prone RNA-binding proteins might contribute very broadly to ALS pathogenesis and the genes identified in our yeast functional screen, coupled with prion-like domain prediction analysis, now provide a powerful resource to facilitate ALS disease gene discovery.
Background
99m
TcTilmanocept, a novel CD206 receptor-targeted radiopharmaceutical, was evaluated in an open-label, phase III trial to determine the false negative rate (FNR) of sentinel lymph node ...biopsy (SLNB) relative to the pathologic nodal status in patients with intraoral or cutaneous head and neck squamous cell carcinoma (HNSCC) undergoing tumor resection, SLNB, and planned elective neck dissection (END). Negative predictive value (NPV), overall accuracy of SLNB, and the impact of radiopharmaceutical injection timing relative to surgery were assessed.
Methods and Findings
This multicenter, non-randomized, single-arm trial (ClinicalTrials.gov identifier NCT00911326) enrolled 101 patients with T1–T4, N0, and M0 HNSCC. Patients received 50 µg
99m
Tctilmanocept radiolabeled with either 0.5 mCi (same day) or 2.0 mCi (next day), followed by lymphoscintigraphy, SLNB, and END. All excised tissues were evaluated for tissue type and tumor presence.
99m
TcTilmanocept identified one or more SLNs in 81 of 83 patients (97.6 %). Of 39 patients identified with any tumor-positive nodes (SLN or non-SLN), one patient had a single tumor-positive non-SLN in whom all SLNs were tumor-negative, yielding an FNR of 2.56 %; NPV was 97.8 % and overall accuracy was 98.8 %. No significant differences were observed between same-day and next-day procedures.
Conclusions
Use of receptor-targeted
99m
Tctilmanocept for lymphatic mapping allows for a high rate of SLN identification in patients with intraoral and cutaneous HNSCC. SLNB employing
99m
Tctilmanocept accurately predicts the pathologic nodal status of intraoral HNSCC patients with low FNR, high NPV, and high overall accuracy. The use of
99m
Tctilmanocept for SLNB in select patients may be appropriate and may obviate the need to perform more extensive procedures such as END.
•Evapotranspiration (ET) was investigated over a 10-year period in a loblolly pine plantation under artificial drainage.•Drought and thinning had limited impacts on ET in the energy-limited coastal ...plain.•The shallow groundwater played a key role in maintaining ET during drought period.•The rapid growth of understory and canopy closure allowed fast recovery of ET after thinning at the warm and wet site.
Managed and natural coastal plain forests in the humid southeastern United States exchange large amounts of water and energy with the atmosphere through the evapotranspiration (ET) process. ET plays an important role in controlling regional hydrology, climate, and ecosystem productivity. However, long-term studies on the impacts of forest management and climatic variability on forest ET are rare, and our understanding of both external and internal drivers on seasonal and interannual ET variability is incomplete. Using techniques centered on an eddy covariance method, the present study measured year-round ET flux and associated hydrometeorological variables in a drained loblolly pine (Pinus taeda L.) plantation on the lower coastal plain of North Carolina, U.S. We found that annual ET was relatively stable (1076 ± 104 mm) in comparison to precipitation (P) (1168 ± 216 mm) during the 10-year study period when the site experienced extreme climate (2007–2008) and forest thinning (2009). At the seasonal time scale, mean ET/P varied between 0.41 and 1.51, with a mean value of 1.12 ± 0.23 and 0.72 ± 0.16 for the growing and dormant seasons, respectively. The extreme drought during 2007–2008 (mean annual P, 854 mm) only resulted in a slight decrease (∼8%) in annual ET owing to the shallow groundwater common to the study area. Although changes in leaf area index and canopy structure were large after the stand was 50% thinned in the fall of 2009, mean annual ET was similar and averaged 1055 mm and 1104 mm before (2005, 2006 and 2009) and after (2010–2015) thinning, respectively. Data suggested that annual ET recovered within two years of the thinning as a result of rapid canopy closure and growth of understory. Further analysis indicated that available energy was the key driver of ET: approximately 69% and 61% of the monthly variations in ET were explained by net radiation during the dormant and growing seasons, respectively. Overall, we concluded that drought and forest thinning had limited impacts on seasonal and annual ET in this energy limited forest ecosystem with shallow groundwater. The results from this study help to better understand regional ecohydrological processes and projecting potential effects of forest management and extreme climate on water and carbon cycles.
Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international ...FTLD-TDP whole-genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1131 unrelated Caucasian patients, we estimated that
C9orf72
repeat expansions and
GRN
loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in
TBK1
(1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the
DPP6
gene led by rs118113626 (
p
value = 4.82e − 08, OR = 2.12), and two known loci:
UNC13A
, led by rs1297319 (
p
value = 1.27e − 08, OR = 1.50) and
HLA
-
DQA2
led by rs17219281 (
p
value = 3.22e − 08, OR = 1.98). While
HLA
represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole-genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (
n
≥ 3) as compared to controls (
n
= 0), we further discovered a possible role for genes functioning within the
TBK1
-related immune pathway (e.g.,
DHX58
,
TRIM21
,
IRF7
) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis.
Background
99m
TcTilmanocept is a CD206 receptor-targeted radiopharmaceutical designed for sentinel lymph node (SLN) identification. Two nearly identical nonrandomized phase III trials compared
99m
...Tctilmanocept to vital blue dye.
Methods
Patients received
99m
Tctilmanocept and blue dye. SLNs identified intraoperatively as radioactive and/or blue were excised and histologically examined. The primary end point, concordance, was the proportion of blue nodes detected by
99m
Tctilmanocept; 90 % concordance was the prespecified minimum concordance level. Reverse concordance, the proportion of radioactive nodes detected by blue dye, was also calculated. The prospective statistical plan combined the data from both trials.
Results
Fifteen centers contributed 154 melanoma patients who were injected with both agents and were intraoperatively evaluated. Intraoperatively, 232 of 235 blue nodes were detected by
99m
Tctilmanocept, for 98.7 % concordance (
p
< 0.001).
99m
TcTilmanocept detected 364 nodes, for 63.7 % reverse concordance (232 of 364 nodes).
99m
TcTilmanocept detected at least one node in more patients (
n
= 150) than blue dye (
n
= 138,
p
= 0.002). In 135 of 138 patients with at least one blue node, all blue nodes were radioactive. Melanoma was identified in the SLNs of 22.1 % of patients; all 45 melanoma-positive SLNs were detected by
99m
Tctilmanocept, whereas blue dye detected only 36 (80 %) of 45 (
p
= 0.004). No positive SLNs were detected exclusively by blue dye. Four of 34 node-positive patients were identified only by
99m
Tctilmanocept, so 4 (2.6 %) of 154 patients were correctly staged only by
99m
Tctilmanocept. No serious adverse events were attributed to
99m
Tctilmanocept.
Conclusions
99m
TcTilmanocept met the prespecified concordance primary end point, identifying 98.7 % of blue nodes. It identified more SLNs in more patients, and identified more melanoma-containing nodes than blue dye.
Background
Sentinel lymph node (SLN) surgery is used worldwide for staging breast cancer patients and helps limit axillary lymph node dissection.
99m
TcTilmanocept is a novel receptor-targeted ...radiopharmaceutical evaluated in 2 open-label, nonrandomized, within-patient, phase 3 trials designed to assess the lymphatic mapping performance.
Methods
A total of 13 centers contributed 148 patients with breast cancer. Each patient received
99m
Tctilmanocept and vital blue dye (VBD). Lymph nodes identified intraoperatively as radioactive and/or blue stained were excised and histologically examined. The primary endpoint, concordance (lower boundary set point at 90 %), was the proportion of nodes detected by VBD and
99m
Tctilmanocept.
Results
A total of 13 centers contributed 148 patients who were injected with both agents. Intraoperatively, 207 of 209 nodes detected by VBD were also detected by
99m
Tctilmanocept for a concordance rate of 99.04 % (
p
< 0.0001).
99m
Tctilmanocept detected a total of 320 nodes, of which 207 (64.7 %) were detected by VBD.
99m
TcTilmanocept detected at least 1 SLN in more patients (146) than did VBD (131,
p
< 0.0001). In 129 of 131 patients with ≥1 blue node, all blue nodes were radioactive. Of 33 pathology-positive nodes (18.2 % patient pathology rate),
99m
Tctilmanocept detected 31 of 33, whereas VBD detected only 25 of 33 (
p
= 0.0312). No pathology-positive SLNs were detected exclusively by VBD. No serious adverse events were attributed to
99m
Tctilmanocept.
Conclusion
99m
TcTilmanocept demonstrated success in detecting a SLN while meeting the primary endpoint. Interestingly,
99m
Tctilmanocept was additionally noted to identify more SLNs in more patients. This localization represented a higher number of metastatic breast cancer lymph nodes than that of VBD.
Pick's disease is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. Pick's disease is pathologically defined by the presence in the frontal ...and temporal lobes of Pick bodies, composed of hyperphosphorylated, three-repeat tau protein, encoded by the MAPT gene. MAPT has two distinct haplotypes, H1 and H2; the MAPT H1 haplotype is the major genetic risk factor for four-repeat tauopathies (eg, progressive supranuclear palsy and corticobasal degeneration), and the MAPT H2 haplotype is protective for these disorders. The primary aim of this study was to evaluate the association of MAPT H2 with Pick's disease risk, age at onset, and disease duration.
In this genetic association study, we used data from the Pick's disease International Consortium, which we established to enable collection of data from individuals with pathologically confirmed Pick's disease worldwide. For this analysis, we collected brain samples from individuals with pathologically confirmed Pick's disease from 35 sites (brainbanks and hospitals) in North America, Europe, and Australia between Jan 1, 2020, and Jan 31, 2023. Neurologically healthy controls were recruited from the Mayo Clinic (FL, USA, or MN, USA between March 1, 1998, and Sept 1, 2019). For the primary analysis, individuals were directly genotyped for the MAPT H1-H2 haplotype-defining variant rs8070723. In a secondary analysis, we genotyped and constructed the six-variant-defined (rs1467967-rs242557-rs3785883-rs2471738-rs8070723-rs7521) MAPT H1 subhaplotypes. Associations of MAPT variants and MAPT haplotypes with Pick's disease risk, age at onset, and disease duration were examined using logistic and linear regression models; odds ratios (ORs) and β coefficients were estimated and correspond to each additional minor allele or each additional copy of the given haplotype.
We obtained brain samples from 338 people with pathologically confirmed Pick's disease (205 61% male and 133 39% female; 338 100% White) and 1312 neurologically healthy controls (611 47% male and 701 53% female; 1312 100% White). The MAPT H2 haplotype was associated with increased risk of Pick's disease compared with the H1 haplotype (OR 1·35 95% CI 1·12 to 1·64, p=0·0021). MAPT H2 was not associated with age at onset (β –0·54 95% CI –1·94 to 0·87, p=0·45) or disease duration (β 0·05 –0·06 to 0·16, p=0·35). Although not significant after correcting for multiple testing, associations were observed at p less than 0·05: with risk of Pick's disease for the H1f subhaplotype (OR 0·11 0·01 to 0·99, p=0·049); with age at onset for H1b (β 2·66 0·63 to 4·70, p=0·011), H1i (β –3·66 –6·83 to –0·48, p=0·025), and H1u (β –5·25 –10·42 to –0·07, p=0·048); and with disease duration for H1x (β –0·57 –1·07 to –0·07, p=0·026).
The Pick's disease International Consortium provides an opportunity to do large studies to enhance our understanding of the pathobiology of Pick's disease. This study shows that, in contrast to the decreased risk of four-repeat tauopathies, the MAPT H2 haplotype is associated with an increased risk of Pick's disease in people of European ancestry. This finding could inform development of isoform-related therapeutics for tauopathies.
Wellcome Trust, Rotha Abraham Trust, Brain Research UK, the Dolby Fund, Dementia Research Institute (Medical Research Council), US National Institutes of Health, and the Mayo Clinic Foundation.
Abstract
Aging-related tau astrogliopathy (ARTAG) is a recently introduced terminology. To facilitate the consistent identification of ARTAG and to distinguish it from astroglial tau pathologies ...observed in the primary frontotemporal lobar degeneration tauopathies we evaluated how consistently neuropathologists recognize (1) different astroglial tau immunoreactivities, including those of ARTAG and those associated with primary tauopathies (Study 1); (2) ARTAG types (Study 2A); and (3) ARTAG severity (Study 2B). Microphotographs and scanned sections immunostained for phosphorylated tau (AT8) were made available for download and preview. Percentage of agreement and kappa values with 95% confidence interval (CI) were calculated for each evaluation. The overall agreement for Study 1 was >60% with a kappa value of 0.55 (95% CI 0.433–0.645). Moderate agreement (>90%, kappa 0.48, 95% CI 0.457–0.900) was reached in Study 2A for the identification of ARTAG pathology for each ARTAG subtype (kappa 0.37–0.72), whereas fair agreement (kappa 0.40, 95% CI 0.341–0.445) was reached for the evaluation of ARTAG severity. The overall assessment of ARTAG showed moderate agreement (kappa 0.60, 95% CI 0.534–0.653) among raters. Our study supports the application of the current harmonized evaluation strategy for ARTAG with a slight modification of the evaluation of its severity.
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