Ultraviolet-Induced Dna Repair Synthesis In Lymphocytes From Patients With Actinic Keratosis

Actinic keratosis is an epidermal cancer in situ. Extensive exposure to sunlight is considered as a contributing factor to the etiology of this tumor. Ultraviolet (UV) light of solar radiation induces structural damage in DNA, which may give rise to mutations and transformed cells if the damage is not repaired. Repair of UV-induced DNA lesions is an essential property of human cells. The conditions so far reported to have defective DNA repair are all associated with an increased incidence of malignancy. Do patients with actinic keratosis also exhibit a reduced capacity to repair UV-induced DNA lesions?DNA repair synthesis in peripheral leukocytes was studied in 10 patients with actinic keratosis and 10 healthy subjects of corresponding age. After irradiation with various doses of UV light the leukocytes were incubated for 2 hr with [3H]thymidine in the presence of hydroxyurea. A dose-response relationship for the UV-induced DNA repair synthesis was established for each individual. The average repair capacity in the patients with actinic keratosis was about 30% below that of the controls. The difference is statistically significant (p < 0.02). Reduced DNA repair synthesis may therefore be an important factor in the etiology of actinic keratosis

Akt kinases in breast cancer and the results of adjuvant therapy

BACKGROUND: The serine/threonine kinase Akt, or protein kinase B, has recently been a focus of interest because of its activity to inhibit apoptosis. It mediates cell survival by acting as a transducer of signals from growth factor receptors that activate phosphatidylinositol 3-kinase. METHODS: We analysed the expression of the isoforms Akt1 and Akt2 as well as phosphorylated Akt (pAkt) by immunohistochemistry in frozen tumour samples from 280 postmenopausal patients who participated in a randomised trial comparing cyclophosphamide–methotrexate–5-fluorouracil chemotherapy and postoperative radiotherapy. The patients were simultaneously randomised to tamoxifen or to no endocrine treatment. RESULTS: Marked staining was found in 24% of the tumours for Akt1, but in only 4% for Akt2. A low frequency of Akt2-positive cells (1–10%) was observed in another 26% of the tumours. pAkt was significantly associated with both Akt1 and Akt2 expression. Overexpression of erbB2 correlated significantly with pAkt (P = 0.0028). The benefit from tamoxifen was analysed in oestrogen receptor (ER)-positive patients. Patients with a negative status of Akt (no overexpression of Akt1, Akt2 or pAkt) showed significant benefit from tamoxifen. The relative rate of distant recurrence, with versus without tamoxifen, was 0.44 (95% confidence interval [CI], 0.25–0.79) for ER+/Akt1- patients, while it was 0.72 (95% CI, 0.34–1.53) for ER+/Akt1+ patients. The difference in rate ratio did not reach statistical significance. The rate of locoregional recurrence was significantly decreased with radiotherapy versus chemotherapy for Akt-negative patients (rate ratio, 0.23; 95% CI, 0.08–0.67; P = 0.0074), while no benefit was evident for the Akt-positive subgroup (rate ratio, 0.77; 95% CI, 0.31–1.9; P = 0.58). The interaction between Akt and the efficacy of radiotherapy was significant in multivariate analysis (P = 0.042). CONCLUSION: Activation of the Akt pathway is correlated with erbB2 overexpression in breast cancer. The results suggest that Akt may predict the local control benefit from radiotherapy

Monthly Incidence Rates of Abusive Encounters for Canadian Family Physicians by Patients and Their Families

Objective. The goal of this study was to examine the monthly incidence rates of abusive encounters for family physicians in Canada. Methods. A 7-page cross-sectional survey. Results. Of the entire study sample (N = 720), 29% of the physicians reported having experienced an abusive event in the last month by a patient or patient family member. Abusive incidents were classified as minor, major, or severe. Of the physician participants who reported having been abused, all reported having experienced a minor event, 26% a major, and 8% a severe event. Of the physicians who experienced an abusive event, 55% were not aware of any policies to protect them, 76% did not seek help, and 64% did not report the abusive event. Conclusion. Family physicians are subjected to significant amounts of abuse in their day-to-day practices. Few physicians are aware of workplace policies that could protect them, and fewer report abusive encounters. Physicians would benefit from increased awareness of institutional policies that can protect them against abusive patients and their families and from the development of a national policy

Study of isotopic fractions and abundances of the neutron-capture elements in HD 175305

The chemical abundances of metal-poor stars are excellent sources of information for setting new constraints on models of Galactic chemical evolution at low metallicities. In this paper we present an attempt to fit the elemental abundances observed in the bright, metal-poor giant HD 175305, and derive isotopic fractions using a parametric model. The observed abundances can be wellmatched by the combined contributions froms- and r-processmaterial. The component coefficients of the r- and s-processes are C1 = 3.220 and C3 = 1.134, respectively. The Smisotopic fraction in this star where the observed neutron-capture elements are produced is predicted to be f 152+154 =0.582,which suggests that, even though the r-process is predominantly responsible for the synthesis of the neutron-capture elements in the early Galaxy, the onset of the s-process had already occurred at this metallicity of [Fe/H] = -1.6

Carrot-based covalently bonded saccharides as a new 2D material for healing defective calcium-silicate-hydrate in cement:Integrating atomistic computational simulation with experimental studies

Concrete is currently produced at a rate of 20 billion tonnes per year and contributes 5-10% of mankind’s CO2 production. If the strength of the calcium-silicate-hydrate (C-SH), the main binding material of concrete, could be improved, the volume of cementitious material needed for a given structure would be reduced and its environmental impact would be decreased. Here, we show that the constitutive behavior of C-S-H can be improved significantly by complexation with carrot-based cellulose nanosheets (CNSs). This environmentally friendly, reinforcing material heals the defective microstructure of C-S-H, which is responsible for structural deformation and failure at larger length scales. CNSs are built from repeating saccharide units that are covalently linked by a β-1-4 glycosidic (C-O-C) bond. The CNSs show remarkable affinity to C-S-H due to the interfacial Ca-O coordination and H-bond interaction. The functional groups on the surface of the CNS sheet act as a root network, cross-linking the neighboring silicate calcium layers and inhibiting the water dynamics at the silicate nanochannel, thereby significantly improving the interfacial properties of the C-SH/CNS hybrid structure. The macro experimental results show that the mechanical properties of the composites increase with increasing the concentration of CNSs up to 0.4-wt%. At 28 days and CNS concentration of 0.20-wt%, the flexural strength increases by about 23.2% and the compressive strength increases by about 17.5%. The C-S-H/CNS composites show significant enhancement in strength, stiffness and ductility, and provide a foundation for the development of new high-performance construction materials with lower carbon footprint

Unprecedented change in the position of four radio sources

Astrometric positions of radio-emitting active galactic nuclei (AGNs) can be determined with sub-milliarcsec accuracy using very long baseline interferometry (VLBI). The usually small apparent proper motion of distant extragalactic targets allow us to realize the fundamental celestial reference frame with VLBI observations. However, long-term astrometric monitoring may reveal extreme changes in some AGN positions. Using new VLBI observations in 2018-2021, we show here that four extragalactic radio sources (3C48, CTA21, 1144+352, 1328+254) have a dramatic shift in their positions by 20-130 milliarcsec over two decades. For all four sources, the apparent positional shift is caused by their radio structure change.Comment: Accepted for publication in MNRA

Observations of radio sources near the Sun

Geodetic Very Long Baseline Interferometry (VLBI) data are capable of measuring the light deflection caused by the gravitational field of the Sun and large planets with high accuracy. The parameter $\gamma$ of the parametrized Post-Newtonian (PPN) formalism estimated using observations of reference radio sources near the Sun should be equal to unity in the general relativity. We have run several VLBI experiments tracking reference radio sources from 1 to 3 degrees from the Sun. The best formal accuracy of the parameter $\gamma$ achieved in the single-session mode is less than 0.01 percent, or better than the formal accuracy obtained with a global solution included all available observations at arbitrary elongation from the Sun. We are planning more experiments starting from 2020 using better observing conditions near the minimum of the Solar activity cycle.Comment: Proceeding of the EVGA 2019 Meeting. arXiv admin note: substantial text overlap with arXiv:1806.1129

Cluster randomised controlled trial to assess a tailored intervention to reduce antibiotic prescribing in rural China:study protocol

INTRODUCTION: Up to 80% of patients with respiratory tract infections (RTI) attending healthcare facilities in rural areas of China are prescribed antibiotics, many of which are unnecessary. Since 2009, China has implemented several policies to try to reduce inappropriate antibiotic use; however, antibiotic prescribing remains high in rural health facilities. METHODS AND ANALYSIS: A cluster randomised controlled trial will be carried out to estimate the effectiveness and cost effectiveness of a complex intervention in reducing antibiotic prescribing at township health centres in Anhui Province, China. 40 Township health centres will be randomised at a 1:1 ratio to the intervention or usual care arms. In the intervention group, practitioners will receive an intervention comprising: (1) training to support appropriate antibiotic prescribing for RTI, (2) a computer-based treatment decision support system, (3) virtual peer support, (4) a leaflet for patients and (5) a letter of commitment to optimise antibiotic use to display in their clinic. The primary outcome is the percentage of antibiotics (intravenous and oral) prescribed for RTI patients. Secondary outcomes include patient symptom severity and duration, recovery status, satisfaction, antibiotic consumption. A full economic evaluation will be conducted within the trial period. Costs and savings for both clinics and patients will be considered and quality of life will be measured by EuroQoL (EQ-5D-5L). A qualitative process evaluation will explore practitioner and patient views and experiences of trial processes, intervention fidelity and acceptability, and barriers and facilitators to implementation. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Biomedical Research Ethics Committee of Anhui Medical University (Ref: 20180259); the study has undergone due diligence checks and is registered at the University of Bristol (Ref: 2020-3137). Research findings will be disseminated to stakeholders through conferences and peer-reviewed journals in China, the UK and internationally. TRIAL REGISTRATION NUMBER: ISRCTN30652037

First-in-human phase 1 study of budigalimab, an anti-PD-1 inhibitor, in patients with non-small cell lung cancer and head and neck squamous cell carcinoma

Publisher Copyright: © 2021, The Author(s).Background: Budigalimab is a humanized, recombinant immunoglobulin G1 monoclonal antibody targeting programmed cell death protein 1 (PD-1). We present the safety, efficacy, pharmacokinetic (PK), and pharmacodynamic data from patients enrolled in the head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC) expansion cohorts of the phase 1 first-in-human study of budigalimab monotherapy (NCT03000257; registered 15 December 2016). Patients and methods: Patients with recurrent/metastatic HNSCC or locally advanced/metastatic NSCLC naive to PD-1/PD-1-ligand inhibitors were enrolled; patients were not selected on the basis of oncogene driver mutations or PD-L1 status. Budigalimab was administered at 250 mg intravenously Q2W or 500 mg intravenously Q4W until disease progression/unacceptable toxicity. The primary endpoints were safety and PK; the secondary endpoint was efficacy. Exploratory endpoints included biomarker assessments. Results: In total, 81 patients were enrolled (HNSCC: N = 41 [PD-L1 positive: n = 19]; NSCLC: N = 40 [PD-L1 positive: n = 16]); median treatment duration was 72 days (range, 1–617) and 71 days (range, 1–490) for the HNSCC and NSCLC cohorts, respectively. The most frequent grade ≥ 3 treatment-emergent adverse event was anemia (HNSCC: n = 9, 22%; NSCLC: n = 5, 13%). Both dosing regimens had comparable drug exposure and increased interferon gamma-induced chemokines, monokine induced by gamma interferon, and interferon-gamma-inducible protein 10. Objective response rates were 13% (90% CI, 5.1–24.5) in the HNSCC cohort and 19% (90% CI, 9.2–32.6) in the NSCLC cohort. Median progression-free survival was 3.6 months (95% CI, 1.7–4.7) and 1.9 months (95% CI, 1.7–3.7) in the HNSCC and NSCLC cohorts. Conclusions: The safety, efficacy and biomarker profiles of budigalimab are similar to other PD-1 inhibitors. Development of budigalimab in combination with novel anticancer agents is ongoing.Peer reviewe