Intracranial internal carotid artery (iICA) calcification is associated with stroke and is often seen as a proxy of atherosclerosis of the intima. However, it was recently shown that these ...calcifications are predominantly located in the tunica media and internal elastic lamina (medial calcification). Intimal and medial calcifications are thought to have a different pathogenesis and clinical consequences and can only be distinguished through ex vivo histological analysis. Therefore, our aim was to develop CT scoring method to distinguish intimal and medial iICA calcification in vivo.
First, in both iICAs of 16 cerebral autopsy patients the intimal and/or medial calcification area was histologically assessed (142 slides). Brain CT images of these patients were matched to the corresponding histological slides to develop a CT score that determines intimal or medial calcification dominance. Second, performance of the CT score was assessed in these 16 patients. Third, reproducibility was tested in a separate cohort.
First, CT features of the score were circularity (absent, dot(s), <90°, 90-270° or 270-360°), thickness (absent, ≥1.5mm, or <1.5mm), and morphology (indistinguishable, irregular/patchy or continuous). A high sum of features represented medial and a lower sum intimal calcifications. Second, in the 16 patients the concordance between the CT score and the dominant calcification type was reasonable. Third, the score showed good reproducibility (kappa: 0.72 proportion of agreement: 0.82) between the categories intimal, medial or absent/indistinguishable.
The developed CT score shows good reproducibility and can differentiate reasonably well between intimal and medial calcification dominance in the iICA, allowing for further (epidemiological) studies on iICA calcification.
Objective:
Cerebral hypoperfusion is among the mechanisms that may explain the association of high blood pressure (BP) with dementia. However, few data are available on the longitudinal association ...of hypertension and cerebral perfusion.
Methods:
We examined the longitudinal association of hypertension, BP, and antihypertensive drugs with change in parenchymal cerebral blood flow (pCBF) in 575 patients with manifest atherosclerotic disease (mean age, 57 ± 10 years) from the SMART‐MR study. Total CBF was measured at baseline and at follow‐up with magnetic resonance (MR) angiography and was expressed per 100ml brain volume as an indicator of cerebral perfusion. Automated brain segmentation was used to quantify brain tissue volumes and cerebrospinal fluid on MR imaging.
Results:
Mean (standard deviation SD) baseline pCBF was 52.3 (9.8) ml/min/100ml and after 3.9 years (range, 3.0–5.8 years) of follow‐up declined to 50.7 (10.3) ml/min/100ml. Regression analyses adjusted for age, sex, follow‐up time, and vascular risk showed that untreated and poorly controlled hypertension and higher levels of systolic and diastolic BP (per SD) were significantly associated with a decline in pCBF; mean differences in decline (95% confidence interval) were −2.2 (−4.4 to 0.0), −1.0 (−1.8 to −0.1), and −1.0 (−1.8 to −0.2) ml/min/100ml. In addition, within hypertensive patients (n = 469), patients using angiotensin receptor blockers (ARBs) did not show a decline in pCBF, whereas patients using other antihypertensive drugs did show a decline in pCBF.
Interpretation:
Untreated hypertension, poorly controlled hypertension, and high BP levels are associated with a decline in pCBF. In addition, treatment with ARBs might result in less decline in pCBF than other antihypertensive treatment.ANN NEUROL 2012
Smoking is a major risk factor for both cancer and chronic obstructive pulmonary disease (COPD). Computed tomography (CT)-based lung cancer screening may provide an opportunity to detect additional ...individuals with COPD at an early stage.
To determine whether low-dose lung cancer screening CT scans can be used to identify participants with COPD.
Single-center prospective cross-sectional study within an ongoing lung cancer screening trial. Prebronchodilator pulmonary function testing with inspiratory and expiratory CT on the same day was obtained from 1140 male participants between July 2007 and September 2008. Computed tomographic emphysema was defined as percentage of voxels less than -950 Hounsfield units (HU), and CT air trapping was defined as the expiratory:inspiratory ratio of mean lung density. Chronic obstructive pulmonary disease was defined as the ratio of forced expiratory volume in the first second to forced vital capacity (FEV(1)/FVC) of less than 70%. Logistic regression was used to develop a diagnostic prediction model for airflow limitation.
Diagnostic accuracy of COPD diagnosis using pulmonary function tests as the reference standard.
Four hundred thirty-seven participants (38%) had COPD according to lung function testing. A diagnostic model with CT emphysema, CT air trapping, body mass index, pack-years, and smoking status corrected for overoptimism (internal validation) yielded an area under the receiver operating characteristic curve of 0.83 (95% CI, 0.81-0.86). Using the point of optimal accuracy, the model identified 274 participants with COPD with 85 false-positives, a sensitivity of 63% (95% CI, 58%-67%), specificity of 88% (95% CI, 85%-90%), positive predictive value of 76% (95% CI, 72%-81%); and negative predictive value of 79% (95% CI, 76%-82%). The diagnostic model showed an area under the receiver operating characteristic curve of 0.87 (95% CI, 0.86-0.88) for participants with symptoms and 0.78 (95% CI, 0.76-0.80) for those without symptoms.
Among men who are current and former heavy smokers, low-dose inspiratory and expiratory CT scans obtained for lung cancer screening can identify participants with COPD, with a sensitivity of 63% and a specificity of 88%.
We related composition of cerebral thrombi to stroke subtype and attenuation on non-contrast CT (NCCT) to gain more insight in etiopathogenesis and to validate thrombus attenuation as a new imaging ...biomarker for acute stroke.
We histopathologically investigated 22 thrombi retrieved after mechanical thrombectomy in acute stroke patients. First, thrombi were classified as fresh, lytic or organized. Second, percentages of red blood cells (RBCs), platelets and fibrin and number of red, white (respectively RBCs or platelets outnumbering other components with ≥ 15%) or mixed thrombi were compared between large artery atherosclerosis (LAA), cardioembolism, dissection and unknown subtype. Third, correlation between attenuation and RBCs, platelets and fibrin was calculated using Pearson's correlation coefficients (r).
Thrombi were fresh in 73% (n = 16), lytic in 18% (n = 4) and organized in 9% (n = 2). The stroke cause was LAA in eight (36%), cardioembolism in six (27%), dissection in three (14%), and unknown in five (23%) patients. LAA thrombi showed the highest percentage RBCs (median 50 (range 35-90)), followed by dissection (35 (20-40), p = 0.05), cardioembolism (35 (5-45), p = 0.013) and unknown subtype (25 (2-40), p = 0.006). No differences in platelets (p = 0.16) and fibrin (p = 0.52) between subtypes were found. LAA thrombi were classified as red or mixed (both n = 4), cardioembolisms as mixed (n = 5) or white (n = 1) and dissection as mixed (n = 3). There was a moderate positive correlation between attenuation and RBCs (r = 0.401, p = 0.049), and weak negative correlations with platelets (r = -0.368, p = 0.09) and fibrin (r = -0.073, p = 0.75).
The majority of cerebral thrombi is fresh. There are no differences in age of thrombi between subtypes. LAA thrombi have highest percentages RBCs, cardioembolism and unknown subtype lowest. No relationship exists between subtype and platelets or fibrin percentages. We found a correlation between the RBC-component and thrombus attenuation, which improves validation of thrombus attenuation on NCCT as an imaging biomarker for stroke management.
The chemical synthesis of a protein from four fragments or more applying native chemical ligation could be achieved stepwise, in one‐pot, convergently, or on a solid support. With the increasing ...demands of applying protein synthesis to highly complex targets, examining these approaches becomes essential to achieve highly efficient synthesis. Different chemical synthetic strategies are compared for the preparation of the H2B protein having different post‐translational modifications. The analogues include H2B that is ubiquitinated at Lys34, Lys120, glycosylated at Ser112, and doubly modified with ubiquitin and N‐acetylglucosamine. This study demonstrates that the applied convergent strategy for the synthesis of most of these complex targets was better than the one‐pot approach in terms of yield and purity. Some guidelines are offered for future synthetic endeavors of similar challenging proteins.
Choose your strategy: Comparison of convergent and one‐pot synthetic approaches to singly or doubly post‐translationally modified H2B protein enables the selection of the most efficient approach to obtain the target proteins in high purity and workable quantities.
Herein, we fabricated bifunctional, noble metal-free, highly efficient nickel/nickel oxide on reduced graphene oxide (Ni/NiO@rGO) by chemical synthesis approach for electrochemical water splitting ...reaction. Its structural and morphological characterization using thermogravimetric analysis (TGA), transmission electron microscopy (TEM), field emission scanning electron microscope (FESEM), energy dispersive analysis of X-ray (EDAX) and X-ray diffraction (XRD) represents, Ni/NiO@rGO is having Ni/NiO NPs ∼10 nm (±2 nm) on graphene oxide with face-centered cubic (FCC) crystal structure. Moreover, the presence of Ni/NiO (2.26%), O (6.56%), N (0.74%) and C (90.44%) from EDAX analysis further confirms the formation of Ni/NiO@rGO and it also supported by FTIR studies. This nanocatalyst is examined further for electrocatalytic water splitting reactions (HER and OER). It demonstrated low overpotential 582 mV to achieve current density at 10 mA cm−2 and smaller Tafel slope of 63 mV dec−1 obtained in 0.5 M H2SO4 towards HER. Also, at the other end at onset potential of 1.6 V vs. RHE towards OER. It demonstrated low overpotential 480 mV to achieve current density at 10 mA cm−2 and smaller Tafel slope of 41 mV dec−1 in 0.5 M KOH towards OER observed. Hydrogen fuel is eco-friendly to the environment and noteworthy performance of earth-saving reactions.
•Ni/NiO@rGO hierarchical nanostructures were synthesized by chemical synthesis method.•Morphological tuning was successfully correlated with synthesis parameters.•Ni/NiO@rGO had highest electrocatalytic activity for overall water splitting reactions.•Oxygen containing sites of GO and of Ni/NiO NPs were less catalytic than Ni/NiO@rGO.•Ni/NiO NPs decoration on GO leading to simultaneous enhancement of stability and activity from their cooperation.
Small ubiquitin like modifier (SUMO) proteins are known to regulate many important cellular processes such as transcription and apoptosis. Recently, hybrid SUMO-ubiquitin chains containing SUMO-2 ...linked to Lys63-di-ubiquitin were found to play a major role in DNA repair. Despite some progress in understanding the role of these hybrid chains in DNA repair, there are various fundamental questions remaining to be answered. To further investigate the importance of hybrid SUMO-ubiquitin chains in DNA repair, the homogenous material of these chains, and their unique analogues, are needed in workable quantities. By applying advanced chemical strategies for protein synthesis, we report the first total chemical synthesis of four different SUMO-2-Lys63-linked di-ubiquitin hybrid chains, in which the di-ubiquitin is linked to different lysines in SUMO. In these syntheses, the usefulness of removable solubilizing tags is demonstrated, and two different approaches were examined in terms of reliability and efficiency. In the first approach, a poly-Arg tag was attached to the C-terminus of SUMO
a 3,4-diaminobenzoic acid cleavable linker, whereas in the second we attached the tag
a phenylacetamidomethyl linker, which can be cleaved by PdCl
. The comparison between these different strategies offers guidelines for future scale-up preparation of these analogues and other proteins, which currently use synthetic peptide intermediates that are difficult to handle and purify. The availability of the SUMO-ubiquitin hybrid chains opens up new opportunities for studying the role of these chains in DNA repair and other cellular processes.
Objectives
To analyse computed tomography (CT) findings of interval and post-screen carcinomas in lung cancer screening.
Methods
Consecutive interval and post-screen carcinomas from the Dutch–Belgium ...lung cancer screening trial were included. The prior screening and the diagnostic chest CT were reviewed by two experienced radiologists in consensus with knowledge of the tumour location on the diagnostic CT.
Results
Sixty-one participants (53 men) were diagnosed with an interval or post-screen carcinoma. Twenty-two (36 %) were in retrospect visible on the prior screening CT. Detection error occurred in 20 cancers and interpretation error in two cancers. Errors involved intrabronchial tumour (
n
= 5), bulla with wall thickening (
n
= 5), lymphadenopathy (
n
= 3), pleural effusion (
n
= 1) and intraparenchymal solid nodules (
n
= 8). These were missed because of a broad pleural attachment (
n
= 4), extensive reticulation surrounding a nodule (
n
= 1) and extensive scarring (
n
= 1). No definite explanation other than human error was found in two cases. None of the interval or post-screen carcinomas involved a subsolid nodule.
Conclusions
Interval or post-screen carcinomas that were visible in retrospect were mostly due to detection errors of solid nodules, bulla wall thickening or endobronchial lesions. Interval or post-screen carcinomas without explanation other than human errors are rare.
Key points
• 22 % of missed carcinomas originally presented as bulla wall thickening on CT.
• 22 % of missed carcinomas originally presented as endobronchial lesions on CT.
• All malignant endobronchial lesions presented as interval carcinomas.
• In the NELSON trial subsolid nodules were not a source of missed carcinomas.
The optimal second- and third-line chemotherapy and targeted therapy for patients with advanced esophagogastric cancer is still a matter of debate. Therefore, a literature search was carried out in ...Medline, EMBASE, CENTRAL, and oncology conferences until January 2016 for randomized controlled trials that compared second- or third-line therapy. We included 28 studies with 4810 patients. Second-line, single-agent taxane/irinotecan showed increased survival compared to best supportive care (BSC) (hazard ratio 0.65, 95 % confidence interval 0.53–0.79). Median survival gain ranged from 1.4 to 2.7 months among individual studies. Taxane- and irinotecan-based regimens showed equal survival benefit. Doublet chemotherapy taxane/irinotecan plus platinum and fluoropyrimidine was not different in survival, but showed increased toxicity
vs
. taxane/irinotecan monotherapy. Compared to BSC, second-line ramucirumab and second- or third-line everolimus and regorafenib showed limited median survival gain ranging from 1.1 to 1.4 months, and progression-free survival gain, ranging from 0.3 to 1.6 months. Third- or later-line apatinib showed increased survival benefit over BSC (HR 0.50, 0.32–0.79). Median survival gain ranged from 1.8 to 2.3 months. Compared to taxane-alone, survival was superior for second-line ramucirumab plus taxane (HR 0.81, 0.68–0.96), and olaparib plus taxane (HR 0.56, 0.35–0.87), with median survival gains of 2.2 and 4.8 months respectively. Targeted agents, either in monotherapy or combined with chemotherapy showed increased toxicity compared to BSC and chemotherapy-alone. This review indicates that, given the survival benefit in a phase III study setting, ramucirumab plus taxane is the preferred second-line treatment. Taxane or irinotecan monotherapy are alternatives, although the absolute survival benefit was limited. In third-line setting, apatinib monotherapy is preferred.
The proteasome, the primary protease for ubiquitin-dependent proteolysis in eukaryotes, is usually found as a mixture of 30S, 26S, and 20S complexes. These complexes have common catalytic sites, ...which makes it challenging to determine their distinctive roles in intracellular proteolysis. Here, we chemically synthesize a panel of homogenous ubiquitinated proteins, and use them to compare 20S and 26S proteasomes with respect to substrate selection and peptide-product generation. We show that 20S proteasomes can degrade the ubiquitin tag along with the conjugated substrate. Ubiquitin remnants on branched peptide products identified by LC-MS/MS, and flexibility in the 20S gate observed by cryo-EM, reflect the ability of the 20S proteasome to proteolyze an isopeptide-linked ubiquitin-conjugate. Peptidomics identifies proteasome-trapped ubiquitin-derived peptides and peptides of potential 20S substrates in Hi20S cells, hypoxic cells, and human failing-heart. Moreover, elevated levels of 20S proteasomes appear to contribute to cell survival under stress associated with damaged proteins.
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