Formation of the Xigaze Metamorphic Sole under Tibetan continental lithosphere reveals generic characteristics of subduction initiation

Metamorphic soles found under allochthonous oceanic lithosphere, or ophiolites, are interpreted as derived from lower plate oceanic crust material accreted to upper plate mantle during intraoceanic subduction initiation. Their metamorphic evolution is inferred to reflect the thermal structure at the site of subduction nucleation, with granulite-bearing soles linked to initiation at hot spreading centers. Here we present garnet Lu-Hf geochronology for the granulite-bearing sole of the Xigaze ophiolite in South Tibet, whose oceanic crust formed ∼130 Ma through continental forearc extension. Our study shows that sole metamorphism was ongoing by 144 Ma, implying that north-directed subduction began at least 14 million years before oceanic forearc spreading. The upper plate at the time of subduction initiation was thus continental, not oceanic. Our results demonstrate that metamorphic characteristics of soles are independent of the specific tectonic setting at the subduction nucleation site and rather provide generic constraints on the subduction initiation process

Formation of the Xigaze Metamorphic Sole under Tibetan continental lithosphere reveals generic characteristics of subduction initiation

Metamorphic soles found under allochthonous oceanic lithosphere, or ophiolites, are interpreted as derived from lower plate oceanic crust material accreted to upper plate mantle during intraoceanic subduction initiation. Their metamorphic evolution is inferred to reflect the thermal structure at the site of subduction nucleation, with granulite-bearing soles linked to initiation at hot spreading centers. Here we present garnet Lu-Hf geochronology for the granulite-bearing sole of the Xigaze ophiolite in South Tibet, whose oceanic crust formed ∼130 Ma through continental forearc extension. Our study shows that sole metamorphism was ongoing by 144 Ma, implying that north-directed subduction began at least 14 million years before oceanic forearc spreading. The upper plate at the time of subduction initiation was thus continental, not oceanic. Our results demonstrate that metamorphic characteristics of soles are independent of the specific tectonic setting at the subduction nucleation site and rather provide generic constraints on the subduction initiation process

Feasibility of ex vivo fluorescence imaging of angiogenesis in (non-) culprit human carotid atherosclerotic plaques using bevacizumab-800CW

Vascular endothelial growth factor-A (VEGF-A) is assumed to play a crucial role in the development and rupture of vulnerable plaques in the atherosclerotic process. We used a VEGF-A targeted fluorescent antibody (bevacizumab-IRDye800CW [bevacizumab-800CW]) to image and visualize the distribution of VEGF-A in (non-)culprit carotid plaques ex vivo. Freshly endarterectomized human plaques (n = 15) were incubated in bevacizumab-800CW ex vivo. Subsequent NIRF imaging showed a more intense fluorescent signal in the culprit plaques (n = 11) than in the non-culprit plaques (n = 3). A plaque received from an asymptomatic patient showed pathologic features similar to the culprit plaques. Cross-correlation with VEGF-A immunohistochemistry showed co-localization of VEGF-A over-expression in 91% of the fluorescent culprit plaques, while no VEGF-A expression was found in the non-culprit plaques (p < 0.0001). VEGF-A expression was co-localized with CD34, a marker for angiogenesis (p < 0.001). Ex vivo near-infrared fluorescence (NIRF) imaging by incubation with bevacizumab-800CW shows promise for visualizing VEGF-A overexpression in culprit atherosclerotic plaques in vivo

The Distinct Metamorphic Stages and Structural Styles of the 1.94–1.86 Ga Snowbird Orogen, Northwest Territories, Canada

Palaeoproterozoic orogenesis within the Archean southeastern Rae craton is related to the initial amalgamation of Laurentia. Characterizing the accompanying tectonic processes during this time has been complicated due to polymetamorphism, which results in the obscuring of the age record of the terranes involved. To improve the knowledge of the tectonic evolution of the South Rae Craton, petrologic and structural analyses are applied in conjunction with in situ trace element chemistry, inclusion barometry, U–Pb monazite and titanite, and Lu–Hf garnet chronology. The data robustly constrain Palaeoproterozoic pressure–temperature–time paths of major deformational events along the southeastern Rae craton margin. D1 occurred between 1.94 and 1.93 Ga in the Dodge-Snowbird domain, which included prograde burial of metasedimentary rocks, deposited at 2.2–2.0 Ga, and the development of migmatitic layering and east-southeast trending folds (S1, F1). Peak metamorphism is recorded in metasedimentary units at c. 1.93 Ga when rocks reached conditions of 9.0–10.5 kbar and 810–830°C. Within the Dodge-Snowbird domain, D2 imparted north-northeast trending open folds and associated axial planar cleavage (S2, F2) between 1.93 and 1.90 Ga during east-west compression that appears to have been synchronous with cooling and exhumation. Later D2 deformation, localized within the Wholdaia Lake shear zone (WLsz; ST1), developed in the footwall of this thrust-sense structure at 1,873 ± 5 Ma at conditions of 9.5–11.0 kbar and 820–850°C. The hangingwall Dodge-Snowbird domain had already cooled to below 300°C by then, indicating a significant structural and metamorphic break across the domain\u27s western boundary. A new phase of unroofing (D3) involved pervasive amphibolite- to greenschist facies extensional shearing (ST2) within the WLsz, which overprinted ST1 foliations between 1.87 and 1.86 Ga. Continued greenschist facies shearing younger than 1.86 Ga likely ended by c. 1.83 Ga when lamprophyre dykes cut the structure, which was followed by cooling until c. 1.80 Ga. This work highlights the utility and application of multiple chronometers (zircon, monazite, titanite, garnet) along with structural and petrologic analysis that together can resolve precise orogenic cycles in polymetamorphic terranes that may otherwise be undetected. The time-resolved P–T–D histories derived here enable more robust interpretations regarding the nature and evolution of 1.9 Ga tectonism along the southeast Rae craton margin, which may be used to refine models for Laurentian terrane amalgamation

Stimulation of the PD-1 pathway decreases atherosclerotic lesion development in Ldlr deficient mice

Signaling through the coinhibitory programmed death (PD)-1/PD-L1 pathway regulates T cell responses and can inhibit ongoing immune responses. Inflammation is a key process in the development of atherosclerosis, the underlying cause for the majority of cardiovascular diseases. Dampening the excessive immune response that occurs during atherosclerosis progression by promoting PD-1/PD-L1 signaling may have a high therapeutic potential to limit disease burden. In this study we therefore aimed to assess whether an agonistic PD-1 antibody can diminish atherosclerosis development.Ldlr-/- mice were fed a western-type diet (WTD) while receiving 100 μg of an agonistic PD-1 antibody or control vehicle twice a week. Stimulation of the PD-1 pathway delayed the WTD-induced monocyte increase in the circulation up to 3 weeks and reduced T cell activation and proliferation. CD4+ T cell numbers in the atherosclerotic plaque were reduced upon PD-1 treatment. More specifically, we observed a 23% decrease in atherogenic IFNγ-producing splenic CD4+ T cells and a 20% decrease in cytotoxic CD8+ T cells, whereas atheroprotective IL-10 producing CD4+ T cells were increased with 47%. Furthermore, we found an increase in regulatory B cells, B1 cells and associated atheroprotective circulating oxLDL-specific IgM levels in agonistic PD-1-treated mice. This dampened immune activation following agonistic PD-1 treatment resulted in reduced atherosclerosis development (p Our data show that stimulation of the coinhibitory PD-1 pathway inhibits atherosclerosis development by modulation of T- and B cell responses. These data support stimulation of coinhibitory pathways as a potential therapeutic strategy to combat atherosclerosis.Biopharmaceutic

Back-Table Fluorescence-Guided Imaging for Circumferential Resection Margin Evaluation Using Bevacizumab-800CW in Patients with Locally Advanced Rectal Cancer

Negative circumferential resection margins (CRM) are the cornerstone for the curative treatment of locally advanced rectal cancer (LARC). However, in up to 18.6% of patients, tumor-positive resection margins are detected on histopathology. In this proof-of-concept study, we investigated the feasibility of optical molecular imaging as a tool for evaluating the CRM directly after surgical resection to improve tumor-negative CRM rates. Methods: LARC patients treated with neoadjuvant chemoradiotherapy received an intravenous bolus injection of 4.5 mg of bevacizumab-800CW, a fluorescent tracer targeting vascular endothelial growth factor A, 2-3 d before surgery (ClinicalTrials.gov identifier: NCT01972373). First, for evaluation of the CRM status, back-table fluorescence guided imaging (FGI) of the fresh surgical resection specimens (n = 8) was performed. These results were correlated with histopathology results. Second, for determination of the sensitivity and specificity of bevacizumab-800CW for tumor detection, a mean fluorescence intensity cutoff value was determined from the formalin-fixed tissue slices (n = 42; 17 patients). Local bevacizumab-800CW accumulation was evaluated by fluorescence microscopy. Results: Back-table FGI correctly identified a tumor-positive CRM by high fluorescence intensities in 1 of 2 patients (50%) with a tumor-positive CRM. For the other patient, low fluorescence intensities were shown, although (sub)millimeter tumor deposits were present less than 1 mm from the CRM. FGI correctly identified 5 of 6 tumor-negative CRM (83%). The 1 patient with false-positive findings had a marginal negative CRM of only 1.4 mm. Receiver operating characteristic curve analysis of the fluorescence intensities of formalin-fixed tissue slices yielded an optimal mean fluorescence intensity cutoff value for tumor detection of 5,775 (sensitivity of 96.19% and specificity of 80.39%). Bevacizumab-800CW enabled a clear differentiation between tumor and normal tissue up to a microscopic level, with a tumor-to-background ratio of 4.7 +/- 2.5 (mean SD). Conclusion: In this proof-of-concept study, we showed the potential of back-table FGI for evaluating the CRM status in LARC patients. Optimization of this technique with adaptation of standard operating procedures could change perioperative decision making with regard to extending resections or applying intraoperative radiation therapy in the case of positive CRM

Potential red-flag identification of colorectal adenomas with wide-field fluorescence molecular endoscopy

Adenoma miss rates in colonoscopy are unacceptably high, especially for sessile serrated adenomas / polyps (SSA/Ps) and in high-risk populations, such as patients with Lynch syndrome. Detection rates may be improved by fluorescence molecular endoscopy (FME), which allows morphological visualization of lesions with high-definition white-light imaging as well as fluorescence-guided identification of lesions with a specific molecular marker. In a clinical proof-of-principal study, we investigated FME for colorectal adenoma detection, using a fluorescently labelled antibody (bevacizumab-800CW) against vascular endothelial growth factor A (VEGFA), which is highly upregulated in colorectal adenomas. Methods: Patients with familial adenomatous polyposis (n = 17), received an intravenous injection with 4.5, 10 or 25 mg of bevacizumab-800CW. Three days later, they received NIR-FME. Results: VEGFA-targeted NIR-FME detected colorectal adenomas at all doses. Best results were achieved in the highest (25 mg) cohort, which even detected small adenomas ( < 3 mm). Spectroscopy analyses of freshly excised specimen demonstrated the highest adenoma-to-normal ratio of 1.84 for the 25 mg cohort, with a calculated median tracer concentration in adenomas of 6.43 nmol/mL. Ex vivo signal analyses demonstrated NIR fluorescence within the dysplastic areas of the adenomas. Conclusion: These results suggest that NIR-FME is clinically feasible as a real-time, red-flag technique for detection of colorectal adenomas

The tubarial salivary glands:A potential new organ at risk for radiotherapy

Introduction: The presence of previously unnoticed bilateral macroscopic salivary gland locations in the human nasopharynx was suspected after visualization by positron emission tomography/computed tomography with prostate-specific membrane antigen ligands (PSMA PET/CT). We aimed to elucidate the characteristics of this unknown entity and its potential clinical implications for radiotherapy. Materials and methods: The presence and configuration of the PSMA-positive area was evaluated in a retrospective cohort of consecutively scanned patients with prostate or urethral gland cancer (n = 100). Morphological and histological characteristics were assessed in a human cadaver study (n = 2). The effect of radiotherapy (RT) on salivation and swallowing was retrospectively investigated using prospectively collected clinical data from a cohort of head-neck cancer patients (n = 723). With multivariable logistic regression analysis, the association between radiotherapy (RT) dose and xerostomia or dysphagia was evaluated. Results: All 100 patients demonstrated a demarcated bilateral PSMA-positive area (average length 4 cm). Histology and 3D reconstruction confirmed the presence of PSMA-expressing, predominantly mucous glands with multiple draining ducts, predominantly near the torus tubarius. In the head-neck cancer patients, the mean RT dose to the gland area was significantly associated with physician-rated posttreatment xerostomia and dysphagia >= grade 2 at 12 months (0.019/gy, 95%CI 0.005-0.033, p =.007; 0.016/gy, 95%CI 0.001-0.031, p =.036). Follow-up at 24 months had similar results. Conclusion: The human body contains a pair of previously overlooked and clinically relevant macroscopic salivary gland locations, for which we propose the name tubarial glands. Sparing these glands in patients receiving RT may provide an opportunity to improve their quality of life. (C) 2020 The Authors. Published by Elsevier B.V

Elevated risk of infection with SARS-CoV-2 Beta, Gamma, and Delta variants compared with Alpha variant in vaccinated individuals

The extent to which severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) break through infection- or vaccine-induced immunity is not well understood. We analyzed 28,578 sequenced SARS-CoV-2 samples from individuals with known immune status obtained through national community testing in the Netherlands from March to August 2021. We found evidence of an increased risk of infection by the Beta (B.1.351), Gamma (P.1), or Delta (B.1.617.2) variants compared with the Alpha (B.1.1.7) variant after vaccination. No clear differences were found between vaccines. However, the effect was larger in the first 14 to 59 days after complete vaccination compared with ≥60 days. In contrast to vaccine-induced immunity, there was no increased risk for reinfection with Beta, Gamma, or Delta variants relative to the Alpha variant in individuals with infection-induced immunity.</p

Implementation and benchmarking of a novel analytical framework to clinically evaluate tumor-specific fluorescent tracers

During the last decade, the emerging field of molecular fluorescence imaging has led to the development of tumor-specific fluorescent tracers and an increase in early-phase clinical trials without having consensus on a standard methodology for evaluating an optical tracer. By combining multiple complementary state-of-the-art clinical optical imaging techniques, we propose a novel analytical framework for the clinical translation and evaluation of tumor-targeted fluorescent tracers for molecular fluorescence imaging which can be used for a range of tumor types and with different optical tracers. Here we report the implementation of this analytical framework and demonstrate the tumor-specific targeting of escalating doses of the near-infrared fluorescent tracer bevacizumab-800CW on a macroscopic and microscopic level. We subsequently demonstrate an 88% increase in the intraoperative detection rate of tumor-involved margins in primary breast cancer patients, indicating the clinical feasibility and support of future studies to evaluate the definitive clinical impact of fluorescence-guided surgery