Carolina Churches Magazine, 1939

Carolina Churches Magazine, Vol. 2, No. 6. Church magazine published out of Grover, NC featuring church histories, news, and devotionals. This issue includes a biography of Col. Frederick Hambright. Featured churches include: Shelby Presbyterian Church, Bethel Presbyterian, and Shiloh Presbyterian. Featured ministers include: R. Z. Johnston, E. P. Davis, T. M. Lowry, W. R. Minter, James Thomas, T. D. Bateman, H. N. McDiarmid, and W. A. Mauney.https://digitalcommons.gardner-webb.edu/fay-webb-gardner-regional-clergy-church-histories/1002/thumbnail.jp

In-Silico Methods for De-Risking the Clinical Development of Subcutaneously Administered Therapeutic Macromolecules

Prediction of human pharmacokinetics (PK) following subcutaneous (SC) administration to animals is challenged by potential interspecies differences in skin anatomy and physiology. With respect to biologic or macromolecule drug development, the SC route is gaining substantial interest as a primary route of drug administration over intravenous due to convenience and cost factors. The bioavailability and time course of a SC administered macromolecule can potentially be influenced by local clearance (CL) processes in the SC space after injection, and due to size constraints, is subject to varying degrees of lymphatic uptake following injection. Traditional allometric techniques employed in interspecies scaling are limited to extrapolation of an average value for PK parameters such as clearance (CL) or volume (V), and provide no information on the time course of a drug after administration. In many cases, PK parameters are estimated using non-compartmental (NCA) methods which, in violation of the assumptions of NCA, requires CL to occur via the sampling compartment. Dedrick plots that have been employed to predict the time course of a drug after administration, do not consider species differences in extravascular drug absorption processes. In contrast, model-based methods such as population based compartmental methods allow for an estimation of absorption processes, along with CL and V, in animals, which can then be scaled to human values according empiric allometric relationships. Physiologically- based PK (PBPK) methods allow for a mechanistic means of accounting for the SC time course and further allow for incorporation of local CL processes and lymphatic transport. Model-based drug development has the potential to minimize reliance on animal data to inform human clinical trial design. Moreover, models developed with an intention to translate animal findings to human scale offer an opportunity to streamline clinical development through trial simulation, thus reducing the time and cost of developing a new therapeutic product. With an aim to de-risk biologic and biosimilar drug development, this thesis describes the development and evaluation of (1) a nonlinear mixed effect model incorporating allometric relationships and (2) a PBPK model incorporating an SC depot compartment, based on a single non-human primate (NHP) species, to predict the PK of a SC administered macromolecule. For reference, model-based methods are compared to traditional allometric and model-independent methods employing the same data used in the model-based approaches. Single-species allometric scaling of CL based on an empiric scaling factor previously demonstrated to support reasonable extrapolation from NHP to humans (i.e. 0.85) failed to predict human CL within a reasonable and pre-determined threshold fold error (i.e. predicted/observed falling with 0.7-1.3). Dedrick plots predicted secondarily-derived PK parameters such as Cmax and Tmax reasonably well, however clearly underperformed in predicting the early portion of the SC time course. Model-based approaches provided reasonable estimation of systemic exposure parameters and prediction of the time course, with PBPK models providing an opportunity to mechanistically appreciate influential factors in the SC time course of a macromolecule. As a novel development the SC time course of a macromolecule could be reasonably simulated by a PBPK model incorporating lymphatic biodistribution and whereby the SC injection was parameterized as a depot compartment within the skin insterstitial space. Similarly for the first time in published literature, a population-based PBPK model was developed incorporating lymphatic system interindividual variability which was demonstrated to predict the time course of a macromolecule in a population of humans

Alternating evolutionary pressure in a genetic algorithm facilitates protein model selection

<p>Abstract</p> <p>Background</p> <p>Automatic protein modelling pipelines are becoming ever more accurate; this has come hand in hand with an increasingly complicated interplay between all components involved. Nevertheless, there are still potential improvements to be made in template selection, refinement and protein model selection.</p> <p>Results</p> <p>In the context of an automatic modelling pipeline, we analysed each step separately, revealing several non-intuitive trends and explored a new strategy for protein conformation sampling using Genetic Algorithms (GA). We apply the concept of alternating evolutionary pressure (AEP), i.e. intermediate rounds within the GA runs where unrestrained, linear growth of the model populations is allowed.</p> <p>Conclusion</p> <p>This approach improves the overall performance of the GA by allowing models to overcome local energy barriers. AEP enabled the selection of the best models in 40% of all targets; compared to 25% for a normal GA.</p

A dyad of lymphoblastic lysosomal cysteine proteases degrades the antileukemic drug L-asparaginase

l-Asparaginase is a key therapeutic agent for treatment of childhood acute lymphoblastic leukemia (ALL). There is wide individual variation in pharmacokinetics, and little is known about its metabolism. The mechanisms of therapeutic failure with l-asparaginase remain speculative. Here, we now report that 2 lysosomal cysteine proteases present in lymphoblasts are able to degrade l-asparaginase. Cathepsin B (CTSB), which is produced constitutively by normal and leukemic cells, degraded asparaginase produced by Escherichia coli (ASNase) and Erwinia chrysanthemi. Asparaginyl endopeptidase (AEP), which is overexpressed predominantly in high-risk subsets of ALL, specifically degraded ASNase. AEP thereby destroys ASNase activity and may also potentiate antigen processing, leading to allergic reactions. Using AEP-mediated cleavage sequences, we modeled the effects of the protease on ASNase and created a number of recombinant ASNase products. The N24 residue on the flexible active loop was identified as the primary AEP cleavage site. Sole modification at this site rendered ASNase resistant to AEP cleavage and suggested a key role for the flexible active loop in determining ASNase activity. We therefore propose what we believe to be a novel mechanism of drug resistance to ASNase. Our results may help to identify alternative therapeutic strategies with the potential of further improving outcome in childhood ALL

Ultrasound-Guided Three-In-One Nerve Block for Femur Fractures

Femur fractures typically affect elderly patients with multiple co-morbidities. Pain control can be difficult, requiring intensive nursing and physician care as elderly patients may manifest cardiovascular and respiratory complications from opiate administration. Ultrasound (US)-guided three-in-one (3-in-1) femoral nerve block (FNB) is an option for pain management in patients with femur fractures, as it provides regional anesthesia to the femoral, obturator and lateral cutaneous nerves. Our goal is to provide medical education regarding the use of US-guided 3-in-1FNB as a rapid and easy procedure that may provide optimal patient care in patients with femur fractures

Acceptability of the Cytosponge procedure for detecting Barrett’s oesophagus: A qualitative study

Objective: To investigate the acceptability of the Cytosponge, a novel sampling device to detect Barrett's oesophagus (BE), a precursor to oesophageal adenocarcinoma (EAC), among people with risk factors for this condition. Design: A qualitative study using semistructured interviews and focus group discussions. Data were explored by three researchers using thematic analysis. Setting: Community setting in London, UK. Participants: A recruitment company identified 33 adults (17 men, 16 women) aged 50–69 years with gastro-oesophageal reflux disease (GERD), a risk factor for BE. The majority of participants were white British (73%). The focus groups were stratified by gender and education. 10 individuals were interviewed and 23 participated in four focus groups. Results: 3 key themes emerged from the data: the anticipated physical experience, preferences for the content of information materials and comparisons with the current gold-standard test. Overall acceptability was high, but there was initial concern about the physical experience of taking the test, including swallowing and extracting the Cytosponge. These worries were reduced after handling the device and a video demonstration of the procedure. Knowledge of the relationship between GERD, BE and EAC was poor, and some suggested they would prefer not to know about the link when being offered the Cytosponge. Participants perceived the Cytosponge to be more comfortable, practical and economical than endoscopy. Conclusions: These qualitative data suggest the Cytosponge was acceptable to the majority of participants with risk factors for BE, and could be used as a first-line test to investigate GERD symptoms. Concerns about the physical experience of the test were alleviated through multimedia resources. The development of patient information materials is an important next step to ensuring patients are adequately informed and reassured about the procedure. Patient stakeholders should be involved in this process to ensure their concerns and preferences are considered

No statistical support for correlation between the positions of protein interaction sites and alternatively spliced regions

BACKGROUND: Alternative splicing is an efficient mechanism for increasing the variety of functions fulfilled by proteins in a living cell. It has been previously demonstrated that alternatively spliced regions often comprise functionally important and conserved sequence motifs. The objective of this work was to test the hypothesis that alternative splicing is correlated with contact regions of protein-protein interactions. RESULTS: Protein sequence spans involved in contacts with an interaction partner were delineated from atomic structures of transient interaction complexes and juxtaposed with the location of alternatively spliced regions detected by comparative genome analysis and spliced alignment. The total of 42 alternatively spliced isoforms were identified in 21 amino acid chains involved in biomolecular interactions. Using this limited dataset and a variety of sophisticated counting procedures we were not able to establish a statistically significant correlation between the positions of protein interaction sites and alternatively spliced regions. CONCLUSIONS: This finding contradicts a naïve hypothesis that alternatively spliced regions would correlate with points of contact. One possible explanation for that could be that all alternative splicing events change the spatial structure of the interacting domain to a sufficient degree to preclude interaction. This is indirectly supported by the observed lack of difference in the behaviour of relatively short regions affected by alternative splicing and cases when large portions of proteins are removed. More structural data on complexes of interacting proteins, including structures of alternative isoforms, are needed to test this conjecture

Effect of second timed appointments for non-attenders of breast cancer screening in England : a randomised controlled trial

BACKGROUND: In England, participation in breast cancer screening has been decreasing in the past 10 years, approaching the national minimum standard of 70%. Interventions aimed at improving participation need to be investigated and put into practice to stop this downward trend. We assessed the effect on participation of sending invitations for breast screening with a timed appointment to women who did not attend their first offered appointment within the NHS Breast Screening Programme (NHSBSP). METHODS: In this open, randomised controlled trial, women in six centres in the NHSBSP in England who were invited for routine breast cancer screening were randomly assigned (1:1) to receive an invitation to a second appointment with fixed date and time (intervention) or an invitation letter with a telephone number to call to book their new screening appointment (control) in the event of non-attendance at the first offered appointment. Randomisation was by SX number, a sequential unique identifier of each woman within the NHSBSP, and at the beginning of the study a coin toss decided whether women with odd or even SX numbers would be allocated to the intervention group. Women aged 50-70 years who did not attend their first offered appointment were eligible for the analysis. The primary endpoint was participation (ie, attendance at breast cancer screening) within 90 days of the date of the first offered appointment; we used Poisson regression to compare the proportion of women who participated in screening in the study groups. All analyses were by intention to treat. This trial is registered with Barts Health, number 009304QM. FINDINGS: We obtained 33 146 records of women invited for breast cancer screening at the six centres between June 2, 2014, and Sept 30, 2015, who did not attend their first offered appointment. 26 054 women were eligible for this analysis (12 807 in the intervention group and 13 247 in the control group). Participation within 90 days of the first offered appointment was significantly higher in the intervention group (2861 [22%] of 12 807) than in the control group (1632 [12%] of 13 247); relative risk of participation 1·81 (95% CI 1·70-1·93; p<0·0001). INTERPRETATION: These findings show that a policy of second appointments with fixed date and time for non-attenders of breast screening is effective in improving participation. This strategy can be easily implemented by the screening sites and, if combined with simple interventions, could further increase participation and ensure an upward shift in the participation trend nationally. Whether the policy should vary by time since last attended screen will have to be considered. FUNDING: National Health Service Cancer Screening Programmes and Department of Health Policy Research Programme

Mammographic density and its interaction with other breast cancer risk factors in an Asian population

10.1038/sj.bjc.6606085British Journal of Cancer1045871-874BJCA