Nature of magnetism in thiol-capped gold nanoparticles investigated with Muon spin rotation

© 2018 Author(s). Muon spin rotation/relaxation measurements show clear evidence for magnetism in 2.2 nm gold nanoparticles capped with butanethiol. At low temperatures (1.8 K), there is significant spin relaxation which decreases as a function of both the applied longitudinal magnetic field and increasing temperature. The results indicate that there are spatially inhomogeneous electronic moments that fluctuate with a wide distribution of correlation times. Possible explanations are discussed

Tissue factor in antiphospholipid antibody-induced pregnancy loss:a pro-inflammatory molecule

Fetal loss in patients with antiphospholipid antibodies (aPL) has been ascribed to thrombosis of placental vessels. However, we have shown that inflammation, specifically complement activation with generation of the anaphylotoxin C5a, is an essential mediator of fetal injury. We have analysed the role of tissue factor (TF) in a mouse model of aPL-induced pregnancy loss. TF is the major cellular activator of the coagulation cascade but also has cell signaling activity. Mice that received aPL-IgG showed strong TF staining throughout the decidua and on embryonic debris. This TF staining was not associated with either fibrin staining or thrombi in deciduas. The absence of fibrin deposition and thrombi suggests that TF-dependent activation of coagulation does not mediate aPL-induced pregnancy loss. We found that either blockade of TF with a monoclonal antibody in wild type mice or a genetic reduction of TF prevented aPL-induced inflammation and pregnancy loss indicated a pathogenic role for TF in aPL-induced pregnancy complications. In response to aPL-generated C5a, neutrophils express TF potentiating inflammation in the deciduas and leading to miscarriages. Importantly, we showed that TF in myeloid cells, but not fetal-derived cells (trophoblasts), was associated with fetal injury, suggesting that the site for pathologic TF expression is neutrophils. We found that TF expression in neutrophils contributes to respiratory burst and subsequent trophoblast injury and pregnancy loss induced by aPL. The identification of TF, acting as an important pro-inflammatory mediator in aPL-induced fetal injury, provides a new target for therapy to prevent pregnancy loss in the aPL syndrome

Increased sensitivity to TRAIL-induced apoptosis occurs during the adenoma to carcinoma transition of colorectal carcinogenesis

The death ligand TRAIL (Apo2L) has potential for cancer therapy, since tumour cells are thought to be more sensitive than normal cells. We investigated whether sensitivity to TRAIL increases during the adenoma to carcinoma transition of colorectal carcinogenesis. Under the same culture conditions, we compared the extent of TRAIL-induced apoptosis in four premalignant adenoma and three carcinoma cell lines. Although TRAIL induced some apoptosis in adenoma cultures, the carcinoma cell lines were significantly more sensitive (P<0.001). This finding was recapitulated in an in vitro model of tumour progression in which conversion of the adenoma cell line AA/C1 to a tumorigenic phenotype was associated with increased TRAIL sensitivity (P<0.001). Increased TRAIL sensitivity during colorectal carcinogenesis has been previously attributed to changes in the balance between TRAIL receptors TRAIL-R1 and -R2 and ‘decoy' receptors TRAIL-R3 and -R4 during malignant progression. To address this, cell surface receptor expression was measured by flow cytometry. In summary, during colorectal carcinogenesis, there is a marked increase in sensitivity to TRAIL-induced apoptosis associated with progression from benign to malignant tumour that could be exploited for colon cancer therapy, but alterations in cell surface TRAIL receptor expression may not be the primary reason for this change

Deleterious Effects of Cold Air Inhalation on Coronary Physiological Indices in Patients With Obstructive Coronary Artery Disease

Background Cold air inhalation during exercise increases cardiac mortality, but the pathophysiology is unclear. During cold and exercise, dual‐sensor intracoronary wires measured coronary microvascular resistance (MVR) and blood flow velocity (CBF), and cardiac magnetic resonance measured subendocardial perfusion. Methods and Results Forty‐two patients (62±9 years) undergoing cardiac catheterization, 32 with obstructive coronary stenoses and 10 without, performed either (1) 5 minutes of cold air inhalation (5°F) or (2) two 5‐minute supine‐cycling periods: 1 at room temperature and 1 during cold air inhalation (5°F) (randomized order). We compared rest and peak stress MVR, CBF, and subendocardial perfusion measurements. In patients with unobstructed coronary arteries (n=10), cold air inhalation at rest decreased MVR by 6% (P=0.41), increasing CBF by 20% (P<0.01). However, in patients with obstructive stenoses (n=10), cold air inhalation at rest increased MVR by 17% (P<0.01), reducing CBF by 3% (P=0.85). Consequently, in patients with obstructive stenoses undergoing the cardiac magnetic resonance protocol (n=10), cold air inhalation reduced subendocardial perfusion (P<0.05). Only patients with obstructive stenoses performed this protocol (n=12). Cycling at room temperature decreased MVR by 29% (P<0.001) and increased CBF by 61% (P<0.001). However, cold air inhalation during cycling blunted these adaptations in MVR (P=0.12) and CBF (P<0.05), an effect attributable to defective early diastolic CBF acceleration (P<0.05) and associated with greater ST‐segment depression (P<0.05). Conclusions In patients with obstructive coronary stenoses, cold air inhalation causes deleterious changes in MVR and CBF. These diminish or abolish the normal adaptations during exertion that ordinarily match myocardial blood supply to demand

Preoperative rectal cancer staging with phased-array MR

<p>Abstract</p> <p>Background</p> <p>We retrospectively reviewed magnetic resonance (MR) images of 96 patients with diagnosis of rectal cancer to evaluate tumour stage (T stage), involvement of mesorectal fascia (MRF), and nodal metastasis (N stage).</p> <p>Our gold standard was histopathology.</p> <p>Methods</p> <p>All studies were performed with 1.5-T MR system (Symphony; Siemens Medical System, Erlangen, Germany) by using a phased-array coil. Our population was subdivided into two groups: the first one, formed by patients at T1-T2-T3, N0, M0 stage, whose underwent MR before surgery; the second group included patients at Tx N1 M0 and T3-T4 Nx M0 stage, whose underwent preoperative MR before neoadjuvant chemoradiation therapy and again 4-6 wks after the end of the treatment for the re-staging of disease.</p> <p>Our gold standard was histopathology.</p> <p>Results</p> <p>MR showed 81% overall agreement with histological findings for T and N stage prediction; for T stage, this rate increased up to 95% for pts of group I (48/96), while for group II (48/96) it decreased to 75%.</p> <p>Preoperative MR prediction of histologically involved MRF resulted very accurate (sensitivity 100%; specificity 100%) also after chemoradiation (sensitivity 100%; specificity 67%).</p> <p>Conclusions</p> <p>Phased-array MRI was able to clearly estimate the entire mesorectal fat and surrounding pelvic structures resulting the ideal technique for local preoperative rectal cancer staging.</p

Chronic widespread bodily pain is increased among individuals with history of fracture:findings from UK Biobank

Acknowledgments This work was supported by grants from the Medical Research Council, British Heart Foundation, Arthritis Research UK, National Osteoporosis Society, International Osteoporosis Foundation, NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, and NIHR Musculoskeletal Biomedical Research Unit, University of Oxford. This research has been conducted using the UK Biobank Resource. Compliance with ethical standards.Peer reviewedPublisher PD

Targeted delivery of a designed sTRAIL mutant results in superior apoptotic activity towards EGFR-positive tumor cells

Previously, we have shown that epidermal growth factor receptor (EGFR)-selective delivery of soluble tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL), by genetic fusion to antibody fragment scFv425, enhances the tumor-selective pro-apoptotic activity of sTRAIL. Insight into the respective contribution of the agonistic receptors TRAIL-R1 and TRAIL-R2 to TRAIL-induced apoptosis may provide a rational approach to further optimize TRAIL-based therapy. Recently, this issue has been investigated using sTRAIL mutants designed to selectively bind to either receptor. However, the relative contribution of the respective TRAIL receptors, in particular TRAIL-R1, in TRAIL signaling is still unresolved. Here, we fused scFv425 to designed sTRAIL mutant sTRAILmR1–5, reported to selectively activate TRAIL-R1, and investigated the therapeutic apoptotic activity of this novel fusion protein. EGFR-specific binding of scFv425:sTRAILmR1–5 potently induced apoptosis, which was superior to the apoptotic activity of scFv425:sTRAIL-wt and a nontargeted MOCK-scFv:sTRAILmR1–5. During cotreatment with cisplatin or the histone deacetylase inhibitor valproic acid, scFv425:sTRAILmR1–5 retained its superior pro-apoptotic activity compared to scFv425:sTRAIL-wt. However, in catching-type Enzyme-Linked ImmunoSorbent Assays with TRAIL-R1:Fc and TRAIL-R2:Fc, scFv425:sTRAILmR1–5 was found to not only bind to TRAIL-R1 but also to TRAIL-R2. Binding to TRAIL-R2 also had functional consequences because the apoptotic activity of scFv425:sTRAILmR1–5 was strongly inhibited by a TRAIL-R2 blocking monoclonal antibody. Moreover, scFv425:sTRAILmR1–5 retained apoptotic activity upon selective knockdown of TRAIL-R1 using small inhibitory RNA. Collectively, these data indicate that both agonistic TRAIL receptors are functionally involved in TRAIL signaling by scFv425:sTRAILmR1–5 in solid tumor cells. Moreover, the superior target cell-restricted apoptotic activity of scFv425:sTRAILmR1–5 indicates its therapeutic potential for EGFR-positive solid tumors

Proteinase-activated receptor 4 stimulation-induced epithelial-mesenchymal transition in alveolar epithelial cells

BACKGROUND: Proteinase-activated receptors (PARs; PAR(1–4)) that can be activated by serine proteinases such as thrombin and neutrophil catepsin G are known to contribute to the pathogenesis of various pulmonary diseases including fibrosis. Among these PARs, especially PAR(4), a newly identified subtype, is highly expressed in the lung. Here, we examined whether PAR(4 )stimulation plays a role in the formation of fibrotic response in the lung, through alveolar epithelial-mesenchymal transition (EMT) which contributes to the increase in myofibroblast population. METHODS: EMT was assessed by measuring the changes in each specific cell markers, E-cadherin for epithelial cell, α-smooth muscle actin (α-SMA) for myofibroblast, using primary cultured mouse alveolar epithelial cells and human lung carcinoma-derived alveolar epithelial cell line (A549 cells). RESULTS: Stimulation of PAR with thrombin (1 U/ml) or a synthetic PAR(4 )agonist peptide (AYPGKF-NH(2), 100 μM) for 72 h induced morphological changes from cobblestone-like structure to elongated shape in primary cultured alveolar epithelial cells and A549 cells. In immunocytochemical analyses of these cells, such PAR(4 )stimulation decreased E-cadherin-like immunoreactivity and increased α-SMA-like immunoreactivity, as observed with a typical EMT-inducer, tumor growth factor-β (TGF-β). Western blot analyses of PAR(4)-stimulated A549 cells also showed similar changes in expression of these EMT-related marker proteins. Such PAR(4)-mediated changes were attenuated by inhibitors of epidermal growth factor receptor (EGFR) kinase and Src. PAR(4)-mediated morphological changes in primary cultured alveolar epithelial cells were reduced in the presence of these inhibitors. PAR(4 )stimulation increased tyrosine phosphorylated EGFR or tyrosine phosphorylated Src level in A549 cells, and the former response being inhibited by Src inhibitor. CONCLUSION: PAR(4 )stimulation of alveolar epithelial cells induced epithelial-mesenchymal transition (EMT) as monitored by cell shapes, and epithelial or myofibroblast marker at least partly through EGFR transactivation via receptor-linked Src activation

Epidemiological analysis of tongue cancer in South Australia for the 24-year period, 1977-2001

The document attached has been archived with permission from the Australian Dental Association. An external link to the publisher’s copy is included.Background: Tongue cancer (141 ICD-9) is the most common intra-oral malignancy in Western countries. In recent decades, reported tongue cancer incidence and mortality rates have increased both in Europe and in the United States, whilst survival has not improved. This study aimed to determine the epidemiology and survival trends of tongue cancer in South Australia over the 24-year period from 1977 to 2001. Methods: Population-based data for tongue cancer were provided by the Central Cancer Registry Unit of the Epidemiology Branch of the South Australian Department of Health. Age-standardized incidence and mortality rates for males and females were calculated. Kaplan-Meier survival analysis was conducted according to time periods, age, sex and tongue sub-sites. Cox regression analysis was used to determine factors that influenced survival. Results: During this 24-year period, 611 cases of tongue cancer (398 males, 213 females) were reported, the majority of which were squamous cell carcinomas. The most common age of diagnosis was 65–69 years in males and 60–64 years in females. Fifty cases (8.18 per cent of all tongue cancer cases) occurred in patients 40 years or younger. The most common cancer sub-sites reported were ‘unspecified site’ (48.45 per cent), lateral border (25.53 per cent) and base (18.49 per cent) of the tongue. The agestandardized incidence and mortality rates for males and females in South Australia were relatively low and stable, and there was no significant improvement in survival of tongue cancer over this period. Significant predictors for survival were sex, age and tongue sub-sites, with male, advanced age and base of tongue associated with poorer survival. Conclusions: Tongue cancer is an important health issue associated with poor survival. Early detection and diagnosis is important in order to improve survival rate for this malignancy.L Lam, RM Logan and C Luk