A Charitable Scheme: William Smith, Michael Schlatter, and the German Free Schools

This thesis describes William Smith’s development of “German Free Schools” in Pennsylvania between 1753-1755. It argues that these schools, ostensibly meant to acclimatize German immigrants to a British colony, were in fact intended to increase pro-Proprietary sympathy, isolate sectarian preachers, and end Quaker dominance over the Pennsylvania General Assembly

Small-scale morphologic properties of martian gullies: insights from analysis of HiRISE images

Abstract not available

Desarrollo de formulado para teñido orgánico con añil

Una investigación ha sido conducida para el desarrollo de un formulado orgánico en el teñido con añil de telas de fibras naturales, el cual sea amigable al medio ambiente, y con cero impacto en la salud de los y las teñidoras. La investigación acá reportada encontró que es posible teñir telas de fibras 100% de algodón con un proceso enteramente orgánico, en donde los componentes del formulado son productos naturales que no causan ningún impacto negativo al medio ambiente, como se detalla a continuación: Afrecho de trigo y melaza como agentes reductores y cal hidratada como agente de control de la alcalinidad. Como se puede observar a continuación, se establecieron los parámetros ideales en la concentración de cada uno de los componentes: tamaño mínimo del baño, orden de mezcla de los componentes, protocolos de los procesos de fermentación y de teñido. Los resultados de teñido demostraron que con el formulado orgánico establecido se pueden teñir telas de 100% algodón con buena solidez al lavado y al frote, con muy poco sangrado posterior de las telas por excedentes de colorante añil

In vitro development of chemotherapy and targeted therapy drug-resistant cancer cell lines: a practical guide with case studies

The development of a drug-resistant cell line can take from 3 to 18 months. However, little is published on the methodology of this development process. This article will discuss key decisions to be made prior to starting resistant cell line development; the choice of parent cell line, dose of selecting agent, treatment interval, and optimizing the dose of drug for the parent cell line. Clinically relevant drug-resistant cell lines are developed by mimicking the conditions cancer patients experience during chemotherapy and cell lines display between two- and eight-fold resistance compared to their parental cell line. Doses of drug administered are low, and a pulsed treatment strategy is often used where the cells recover in drug-free media. High-level laboratory models are developed with the aim of understanding potential mechanisms of resistance to chemotherapy agents. Doses of drug are higher and escalated over time. It is common to have difficulty developing stable clinically relevant drug-resistant cell lines. A comparative selection strategy of multiple cell lines or multiple chemotherapeutic agents mitigates this risk and gives insight into which agents or type of cell line develops resistance easily. Successful selection strategies from our research are presented. Pulsed-selection produced platinum or taxane-resistant large cell lung cancer (H1299 and H460) and temozolomide-resistant melanoma (Malme-3M and HT144) cell lines. Continuous selection produced a lapatinib-resistant breast cancer cell line (HCC1954). Techniques for maintaining drug-resistant cell lines are outlined including; maintaining cells with chemotherapy, pulse treating with chemotherapy, or returning to master drug-resistant stocks. The heterogeneity of drug-resistant models produced from the same parent cell line with the same chemotherapy agent is explored with reference to P-glycoprotein. Heterogeneity in drug-resistant cell lines reflects the heterogeneity that can occur in clinical drug resistance

Staff experience of harassment and stalking behaviour by patients

Staff from one National Health Service (NHS) Trust in England completed an online survey (N = 590) about their experience of intrusive behaviours from patients. These experiences were categorised into either stalking or harassment and compared in terms of staff and patient characteristics, types of intrusions, and aftermath. Overall, 150 were classified as being stalked (25.4%) and 172 harassed (29.2%). There were no differences in staff characteristics between the two groups. Staff from forensic services and nursing staff were particularly susceptible to these intrusions which took many forms. Respondents perceived a range of causes for the stalking and harassment, the most common being to gain power and control/to scare. It was rare for legal sanctions to be brought against the patient. Our findings reinforce the need for service providers to have policies supported with preventative measures, education and a robust process for addressing stalking so that these measures are embedded in practice in a way that supports staff working with patients. Furthermore, service providers should be challenged on what steps they have taken to prevent, and monitor, such behaviour

miR-630 targets IGF1R to regulate response to HER-targeting drugs and overall cancer cell progression in HER2 over-expressing breast cancer

Background: While the treatment of HER2 over-expressing breast cancer with recent HER-targeted drugs has been highly effective for some patients, primary (also known as innate) or acquired resistance limits the success of these drugs. microRNAs have potential as diagnostic, prognostic and predictive biomarkers, as well as replacement therapies. Here we investigated the role of microRNA-630 (miR-630) in breast cancer progression and as a predictive biomarker for response to HER-targeting drugs, ultimately yielding potential as a therapeutic approach to add value to these drugs. Methods: We investigated the levels of intra- and extracellular miR-630 in cells and conditioned media from breast cancer cell lines with either innate- or acquired- resistance to HER-targeting lapatinib and neratinib, compared to their corresponding drug sensitive cell lines, using qPCR. To support the role of miR-630 in breast cancer, we examined the clinical relevance of this miRNA in breast cancer tumours versus matched peritumours. Transfection of miR-630 mimics and inhibitors was used to manipulate the expression of miR-630 to assess effects on response to HER-targeting drugs (lapatinib, neratinib and afatinib). Other phenotypic changes associated with cellular aggressiveness were evaluated by motility, invasion and anoikis assays. TargetScan prediction software, qPCR, immunoblotting and ELISAs, were used to assess miR-630’s regulation of mRNA, proteins and their phosphorylated forms. Results: We established that introducing miR-630 into cells with innate- or acquired- resistance to HER-drugs significantly restored the efficacy of lapatinib, neratinib and afatinib; through a mechanism which we have determined to, at least partly, involve miR-630’s regulation of IGF1R. Conversely, we demonstrated that blocking miR-630 induced resistance/insensitivity to these drugs. Cellular motility, invasion, and anoikis were also observed as significantly altered by miR-630 manipulation, whereby introducing miR-630 into cells reduced cellular aggression while inhibition of miR-630 induced a more aggressive cellular phenotype. Conclusions: Taken together, our findings suggest miR-630 as a key regulator of cancer cell progression in HER2 over-expressing breast cancer, through targeting of IGF1R. This study supports miR-630 as a diagnostic and a predictive biomarker for response to HER-targeted drugs and indicates that the therapeutic addition of miR-630 may enhance and improve patients’ response to HER-targeting drugs

Clinical performance of bleeding risk scores for predicting major and clinically relevant non-major bleeding events in patients receiving warfarin

Background: Oral anticoagulant therapy is associated with an increased risk of hemorrhage, which can be assessed by bleeding risk scores. We evaluated the performance of five validated scores for predicting major and clinically relevant non-major bleeding events in patients receiving warfarin. Methods and results: We conducted an ambispective, single-center cohort study of 321 consecutive patients enrolled in an academic anticoagulation clinic. The following scores were calculated: modified Outpatient Bleeding Risk Index, Contemporary Bleeding Risk Model, HEMORR2HAGES (Hepatic or Renal Disease, Ethanol Abuse, Malignancy, Older Age, Reduced Platelet Count or Function, Re-Bleeding, Hypertension, Anemia, Genetic Factors, Excessive Fall Risk and Stroke), ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation), and HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile International Normalized Ratio, Elderly, Drugs/Alcohol). Main outcomes were major bleeding and a composite of major plus clinically relevant non-major bleeding. Incidence rates for all group were 3.8 (95% confidence interval [CI] 2.0-6.4) and 11.9 (95% CI 8.6-16.4) events per 100 patient-years for major bleeding and major plus clinically relevant non-major bleeding, respectively. Agreement among the five scores was low to moderate (Kendall\u27s tau-b coefficients 0.22-0.54). For major bleeding, the c-statistics ranged from 0.606 to 0.735, whereas for major plus clinically relevant non-major bleeding, they ranged from 0.549 to 0.613. For all scores, the 95% CI for the c-statistics crossed 0.5 or was very close. Among high-risk patients, the hazard ratios for major bleeding ranged from 0.90 to 39.01, whereas for major plus clinically relevant non-major bleeding, they ranged from 1.52 to 8.71. For intermediate-risk patients, no score, except the Contemporary Bleeding Risk Model, produced statistically significant hazard ratios. Conclusion: The scores demonstrated poor agreement and low to moderate discriminatory ability. General clinical implementation of these scores cannot be recommended yet. © 2013 International Society on Thrombosis and Haemostasis