Formulation predictive dissolution (fPD) testing to advance oral drug product development: an introduction to the US FDA funded ‘21st Century BA/BE’ project

Over the past decade, formulation predictive dissolution (fPD) testing has gained increasing attention. Another mindset is pushed forward where scientists in our field are more confident to explore the in vivo behavior of an oral drug product by performing predictive in vitro dissolution studies. Similarly, there is an increasing interest in the application of modern computational fluid dynamics (CFD) frameworks and high-performance computing platforms to study the local processes underlying absorption within the gastrointestinal (GI) tract. In that way, CFD and computing platforms both can inform future PBPK-based in silico frameworks and determine the GI-motility-driven hydrodynamic impacts that should be incorporated into in vitro dissolution methods for in vivo relevance. Current compendial dissolution methods are not always reliable to predict the in vivo behavior, especially not for biopharmaceutics classification system (BCS) class 2/4 compounds suffering from a low aqueous solubility. Developing a predictive dissolution test will be more reliable, cost-effective and less time-consuming as long as the predictive power of the test is sufficiently strong. There is a need to develop a biorelevant, predictive dissolution method that can be applied by pharmaceutical drug companies to facilitate marketing access for generic and novel drug products. In 2014, Prof. Gordon L. Amidon and his team initiated a far-ranging research program designed to integrate (1) in vivo studies in humans in order to further improve the understanding of the intraluminal processing of oral dosage forms and dissolved drug along the gastrointestinal (GI) tract, (2) advancement of in vitro methodologies that incorporates higher levels of in vivo relevance and (3) computational experiments to study the local processes underlying dissolution, transport and absorption within the intestines performed with a new unique CFD based framework. Of particular importance is revealing the physiological variables determining the variability in in vivo dissolution and GI absorption from person to person in order to address (potential) in vivo BE failures. This paper provides an introduction to this multidisciplinary project, informs the reader about current achievements and outlines future directions

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Current Antimicrobial Use in Horses Undergoing Exploratory Celiotomy: A Survey of Board-Certified Equine Specialists

In the past decade, there has been a considerable increase in the recognition of antimicrobial resistance in equine practice. The objective of this study was to survey the current clinical use of antimicrobials for a commonly performed surgical procedure (exploratory celiotomy) with the goal of understanding how recent literature and changes in microbial resistance patterns may have impacted antimicrobial selection practices. An electronic survey was distributed to veterinary professionals within the American College of Veterinary Internal Medicine (ACVIM) and the American College of Veterinary Surgery (ACVS). A total of 113 completed surveys were returned. Practitioners reported antimicrobials were most frequently given 30–60 min preoperatively (63.1%). Two antimicrobial classes were typically administered (95.5%), with gentamicin (98.2%) and potassium penicillin (74.3%) being the most common. Antimicrobials were typically not re-dosed intraoperatively (78.6%). Factors that affected overall treatment length postoperatively included resection (81.4%), bloodwork (75.2%), enterotomy (74.3%), fever (85.0%), incisional complications (76.1%), and thrombophlebitis (67.3%). The most common duration of antimicrobial use was 1–3 d for non-strangulating lesions (54.4% of cases) and inflammatory conditions such as enteritis or peritonitis (50.4%), and 3–5 d for strangulating lesions (63.7%). Peri-incisional and intra-abdominal antimicrobials were used by 24.8% and 11.5% of respondents, respectively. In summary, antimicrobial usage patterns were highly variable among practitioners and, at times, not concordant with current literature

The Effects of Antimicrobial Protocols and Other Perioperative Factors on Postoperative Complications in Horses Undergoing Celiotomy: A Retrospective Analysis, 2008–2021

Recognition of antimicrobial resistance in equine practice has increased over the past decade. The objective of this study was to provide an updated retrospective review of antimicrobial regimens in one tertiary referral hospital and to evaluate the association with postoperative complications. A secondary objective was to evaluate other perioperative factors including surgical procedure, anesthetic and recovery parameters, and the effect of perioperative medications on complications and outcomes. A computerized search of medical records was performed to identify horses undergoing exploratory celiotomy from 1 January 2008 to 31 December 2021. A total of 742 celiotomies were performed (608 completed, 134 terminated intraoperatively). Factors recorded were evaluated using logistic regression for the presence of either incisional infection, postoperative ileus, or other complications postoperatively. Antimicrobial type or timing (pre-, intra-, or postoperative) were not associated with decreased risk of incisional infection or postoperative ileus; however, the duration of NSAID use was positively associated with incisional infection (OR 1.14 per day). Lidocaine and alpha-2-agonist administration postoperatively were also associated with increased incidence of postoperative ileus (OR 21.5 and 1.56, respectively). Poor recovery quality (OR 4.69), the addition of other antimicrobials besides penicillin/gentamicin postoperatively (OR 3.63), and an increased number of different NSAID classes used (OR 1.46 per additional) were associated with other complications. Implementation of enterotomy was associated with decreased risk of other complications (OR 0.64). These findings provide an updated summary of factors associated with postoperative complications in horses undergoing celiotomy

Pan-cancer landscape of CD274 (PD-L1) copy number changes in 244 584 patient samples and the correlation with PD-L1 protein expression

Introduction Several studies have shown clinical outcomes data that support the use of CD274 (PD-L1) copy-number (CN) gains and/or losses as a biomarker for immune checkpoint inhibitor (ICPI). Here, we present the landscape of CD274 CN changes across a large cohort of solid tumor cases and correlate these with PD-L1 protein expression by immunohistochemistry.Methods We analyzed all cases that underwent comprehensive genomic profiling (CGP) testing at Foundation Medicine between August 2014 and June 2020. CD274 CN changes were correlated with PD-L1 expression in tumor types where there were Food and Drug Administration approved companion diagnostic (CDx) claims and the CDx assay was used to assess PD-L1 expression.Results In all, 244 584 samples representing 290 solid tumor types were included in the study. Overall, 17.6% (42 983/244 584) had CD274 CN gains (>specimen ploidy), 44.6% (108 970/244 584) were CD274 CN neutral, and 37.9% (92 631/244 584) had CD274 CN loss. Using different CN cut offs to define CD274 positivity resulted in different prevalence estimates: ploidy +1, 17.4% (42 636/244 584); ploidy +2, 6.2% (15 183/244 584); ploidy +3, 2.2% (5375/244 584); ploidy +4, 1.1% (2712/244 584); and ploidy +8, 0.2% (434/244 584). The prevalence of CN changes and CN positivity varied based on tumor type. CD274 CN gains were significantly associated with PD-L1 positivity in NSCLC, urothelial carcinoma, breast carcinoma, cervical carcinoma, esophagus squamous cell carcinoma (SCC) and head and neck SCC (ORs 3.3, 3.0, 2.0, 4.5. 3.8, 8.4, 1.4, respectively; p<0.05) and with microsatellite instability status in only clinically relevant tumor types (gastric adenocarcinoma, colorectal adenocarcinoma, uterine endometrial adenocarcinoma, esophageal adenocarcinoma and gastroesophageal junction adenocarcinoma (OR: 5.2, 1.9, 3.2, 3.7 and 6.5, respectively; p<0.05)). Conversely, CD274 CN changes were not significantly correlated with tumor mutational burden in almost all the tumor types.Conclusion CD274 CN changes and PD-L1 expression were highly correlated in multiple tumor types. These prevalence data on CD274 CN changes across a large cohort of different solid tumors can be used to design future clinical studies to assess whether CD274 CN changes could be a potential biomarker for ICPI

A Culturally Sensitive Instrument Measuring Variables Related to

This dissertation is dedicated to my parents, Robert Lee Houston and Rosemary Houston, my strength, my courage, my pillars and to my the rest of my family and great friends who have supported me, guided me, mentored me, and inspired me in achieving all of my goals and successes. ii ACKNOWLEDGEMENTS In writing this dissertation, there were many people who provided unconditional support and encouragement that lead to this final product. I would first like to thank my dissertation committee John Lounsbury (chair), Tricia McClam, Ph.D., Jacob Levy, Ph.D. and Richard Saudargus, Ph.D. who provided continuous comments and suggestions on my dissertation project that improved and expanded the scope of the paper. I would especially like to thank my chair, my adviser, and most importantly my mentor John Lounsbury, whose belief and confidence in my ability to accomplish all of the goals I set for myself, got me to this point. John’s words of encouragement and support have resonated with me since I began my Ph.D. program. He has provided more support and guidance then any graduate student could ask for. Thank you again John. I would like t

What Favorite Teacher Research Says: Implement Dispositional Growth Plans!

In an effort to further evaluate the effect of educator dispositions, favoriteteachers.org asks people to recall memories of their favorite teacher and list the first characteristic that comes to mind about them. Ongoing research shows that between knowledge, skills, and dispositions of former teachers the greatest factor in determining what makes a teacher someone’s favorite is that the teacher they chose possessed certain dispositional traits. Identifying teacher disposition as the most important factor in favorite teachers, we can examine ways to increase these traits in new, current, and even experienced educators. The benefits of implementing dispositional growth plans may translate into an increase in achievement while saving time and money for the schools. With more teachers demonstrating the desired dispositional traits of favorite teachers, student interest, attendance, and motivation could translate into increased student performance and success. Promoting these desired traits with the development of dispositional growth plans may also increase teacher satisfaction and help to meet the personal and professional needs that many teachers cite as areas of neglect and reasons for quitting the profession. With more than forty percent of new teachers leaving the profession in the first five years, the cost savings to districts and states in reducing attrition could be a real cost savings while promoting an environment more conducive to academic and personal growth for students and teachers alike

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PAM, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and pArg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM(-/-) patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors