Modeling the impact of amino acid substitution in a monoclonal antibody on cation exchange chromatography

A vital part of biopharmaceutical research is decision making around which lead candidate should be progressed in early-phase development. When multiple antibody candidates show similar biological activity, developability aspects are taken into account to ease the challenges of manufacturing the potential drug candidate. While current strategies for developability assessment mainly focus on drug product stability, only limited information is available on how antibody candidates with minimal differences in their primary structure behave during downstream processing. With increasing time-to-market pressure and an abundance of monoclonal antibodies (mAbs) in development pipelines, developability assessments should also consider the ability of mAbs to integrate into the downstream platform. This study investigates the influence of amino acid substitutions in the complementarity-determining region (CDR) of a full-length IgG1 mAb on the elution behavior in preparative cation exchange chromatography. Single amino acid substitutions within the investigated mAb resulted in an additional positive charge in the light chain (L) and heavy chain (H) CDR, respectively. The mAb variants showed an increased retention volume in linear gradient elution compared with the wild-type antibody. Furthermore, the substitution of tryptophan with lysine in the H-CDR3 increased charge heterogeneity of the product. A multiscale in silico analysis, consisting of homology modeling, protein surface analysis, and mechanistic chromatography modeling increased understanding of the adsorption mechanism. The results reveal the potential effects of lead optimization during antibody drug discovery on downstream processing

Morphometric characteristics of pyloric gastric glands at experimental acute gastritis and after administration of ‘Platex-Placental’ medication on the background of experimental acute gastritis

В роботі встановлена динаміка змін середніх метричних показників воротарних залоз шлунка при гострому експериментальному гастриті, після введення препарату «Платекс-плацентарний» (кріоконсервована тканина плаценти) та після введення препарату «Платекс-плацентарний» на тлі гострого експериментального гастриту. Виявлена позитивна динаміка дії препарату «Платекс-плацентарний» на швидкість перебігу та перебудову захисних властивостей воротарних залоз у відповідь на гострий запальний процес.; В работе установлена динамика изменений средних показателей привратниковых желез желудка при остром экспериментальном гастрите, после введения препарата «Платекс-плацентарный» (криоконсервированная ткань плаценты) и после введения препарата «Платекс-плацентарный» на фоне острого экспериментального гастрита. Выявлена положительная динамика действия препарата «Платекс-плацентарный» на скорость протекания и перестройку защитных свойств привратниковых желез в ответ на острый воспалительный процесс.; The study descrides the dynamics of changes in average indices of pyloric gastric glands at experimental acute gastritis, after administration of ‘Platex-Placental’ medication, and after administration of ‘Platex-Placental’ medication on a background of experimental acute gastritis. The positive outcomes were found after administration of ‘Platex-Placental’ medication in terms of inflammation course as well as reorganization of defence peculiarities of pyloric glands as a response to an acute inflammation

A Randomized Controlled Trial of a Faith-Placed, Lay Health Advisor Delivered Smoking Cessation Intervention for Rural Residents

Introduction. Rural US residents smoke at higher rates than urban or suburban residents. We report results from a community-based smoking cessation intervention in Appalachian Kentucky. Study design. Single-blind, group-randomized trial with outcome measurements at baseline, 17 weeks and 43 weeks. Setting/participants. This faith-placed CBPR project was located in six counties of rural Appalachian Kentucky. A total of 590 individual participants clustered in 28 churches were enrolled in the study. Intervention. Local lay health advisors delivered the 12-week Cooper/Clayton Method to Stop Smoking program, leveraging sociocultural factors to improve the cultural salience of the program for Appalachian smokers. Participants met with an interventionist for one 90 min group session once per week incorporating didactic information, group discussion, and nicotine replacement therapy. Main outcome measures. The primary outcome was self-reported smoking status. Secondary outcomes included Fagerström nicotine dependence, self-efficacy, and decisional balance. Results. With post-intervention data from 92% of participants, those in intervention group churches (N = 383) had 13.6 times higher odds of reporting quitting smoking one month post-intervention than participants in attention control group churches (N = 154, p \u3c 0.0001). In addition, although only 3.2% of attention control group participants reported quitting during the control period, 15.4% of attention control participants reported quitting smoking after receiving the intervention. A significant dose effect of the 12-session Cooper/Clayton Method was detected: for each additional session completed, the odds of quitting smoking increased by 26%. Conclusions. The Cooper/Clayton Method, delivered in rural Appalachian churches by lay health advisors, has strong potential to reduce smoking rates and improve individuals\u27 health

Terminate Lung Cancer (TLC) Study—A Mixed-Methods Population Approach to Increase Lung Cancer Screening Awareness and Low-Dose Computed Tomography in Eastern Kentucky

For low dose CT lung cancer screening to be effective in curbing disease mortality, efforts are needed to overcome barriers to awareness and facilitate uptake of the current evidence-based screening guidelines. A sequential mixed-methods approach was employed to design a screening campaign utilizing messages developed from community focus groups, followed by implementation of the outreach campaign intervention in two high-risk Kentucky regions. This study reports on rates of awareness and screening in intervention regions, as compared to a control region

Exploring the role of gender and risk perceptions in people's decisions to register as a bone marrow donor

Increasing the number of bone marrow (BM) donors is important to ensure sufficient diversity on BM registries to meet the needs of patients. This study used an experimental approach to test the hypothesis that providing information about the risks of BM donation to allay unsubstantiated fears would reduce male and female participants’ perceptions of risk for donation and joining the Australian BM Donor Registry (ABMDR). Males’ and females’ intentions to register on the ABMDR, their attitudes, norms, and perceived behavioural control (efficacy) in relation to registering were explored also. Participants were allocated randomly to either a risk (exposed to risk information about BM donation) or no risk(not exposed to risk information) condition. In partial support of hypotheses, exposure to risk information did reduce perceived risk for registering on the ABMDR for males only. Participants in the risk condition also demonstrated lower scores on attitude (males only) and intention compared to participants in the no risk condition. These findings highlight the complex role of risk perceptions and gender differences in understanding people’s decisions to join a BM registry

Individual decision making about lung cancer screening: A conjoint analysis of perspectives among a high‐risk national sample

Objectives Lung cancer screening (LCS) is effective in reducing lung cancer mortality, but there is limited information available regarding preferences among high-risk individuals concerning LCS. In this study, we use a conjoint valuation analysis (CVA) to better understand which LCS attributes most affect LCS preferences. Materials and Methods We implemented a web-based nationally representative survey that included a full-profile CVA exercise. Participants were over the age of 45, had at least a 20 pack-year smoking history, and no history of lung cancer. The CVA instrument included five LCS attributes, and additional survey items collected demographic and psychosocial information. Results Participants (n = 210) had a mean age of 61 (SD 8.5) years, approximately half were female (51.9%), and were racially/ethnically diverse. Average relative importance of the LCS program attributes was (from high to low): out of pocket costs (27.3 +/- 17.7); provider recommendation (24.8 +/- 13.4); mortality reduction (17.2 +/- 8.9); false-positive rate (15.8 +/- 10.4); and ease of access (14.8 +/- 7.3). There was large variation among individuals, but few significant associations of propensity to screen with individual demographic characteristics. Average screening propensity across individuals (1-9 scale) was 3.63 +/- 1.6, and average rates of individual scenarios ranged from 2.60 +/- 2.00 to 5.57 +/- 2.13, indicating low inclination for screening. Conclusions We found that overall propensity for screening is low in a high-risk population, and that out of pocket costs were of greater importance to potential screeners than mortality reduction or false-positive rates. Thus, individuals considering or eligible for LCS need additional education and support regarding the LCS landscape in order to achieve informed decision making

Brief Education and a Conjoint Valuation Survey May Reduce Decisional Conflict Regarding Lung Cancer Screening

Background. Recent data and policy decisions have led to the availability of lung cancer screening (LCS) for individuals who are at increased risk of developing lung cancer. In establishing implementation policies, the US Preventive Services Task Force recommended and the Centers for Medicare and Medicaid Services required that individuals who meet eligibility criteria for LCS receive a patient counseling and shared decision-making consultation prior to LCS. Methods. This study evaluated the potential of a values clarification/preference elicitation exercise and brief educational intervention to reduce decisional conflict regarding LCS. Participants ( N = 210) completing a larger online survey responded to a measure of decisional conflict prior to and following administration of a conjoint survey and brief educational narrative about LCS. The conjoint survey included 22 choice sets (two of which were holdout cards), incorporating 5 attributes with 17 levels. Results. Results pertaining to changes in decisional conflict showed that participants reported statistically significantly and clinically meaningful reductions in decisional conflict following administration of the brief educational narrative and conjoint survey across the total score (Δ = 29.30; d = 1.09) and all four decisional conflict subscales: Uncertainty (Δ = 27.75; d = 0.73), Informed (Δ = 35.32; d = 1.11), Values Clarity (Δ = 31.82; d = 0.85), and Support (Δ = 18.78; d = 0.66). Discussion. While the study design precludes differentiating the effects of the brief educational narrative and the conjoint survey, data suggest that these tools offer a reasonable approach to clarifying personal beliefs and perspectives regarding LCS participation. Given the complicated nature of LCS decisions and recent policies advocating informed and shared decision-making approaches, conjoint surveys should be evaluated as one of the tools that could help individuals make choices about LCS participation