A PKPD Case Study: Achieving Clinically Relevant Exposures of AZD5991 in Oncology Mouse Models.

Capturing human equivalent drug exposures preclinically is a key challenge in the translational process. Motivated by the need to recapitulate the pharmacokinetic (PK) profile of the clinical stage Mcl-1 inhibitor AZD5991 in mice, we describe the methodology used to develop a refined mathematical model relating clinically relevant concentration profiles to efficacy. Administration routes were explored to achieve target exposures matching the clinical exposure of AZD5991.

A Pilot Phase I Trial of Allogeneic Umbilical Cord Tissue-Derived Mesenchymal Stromal Cells in Neonates With Hypoxic-Ischemic Encephalopathy.

Hypoxic ischemic encephalopathy (HIE) in neonates causes increased mortality and long-term morbidity in surviving babies. Hypothermia (HT) has improved outcomes, however, mortality remains high with ~half of surviving babies developing neurological impairment in their first years. We previously explored the use of autologous cord blood (CB) to determine if CB cells could lessen long-term damage to the brain.

Feasibility Study of Cord Tissue Derived Mesenchymal Stromal Cells in COVID-19-Related Acute Respiratory Distress Syndrome.

Background: Treatment options for patients with COVID-19-related acute respiratory distress syndrome (ARDS) are desperately needed. Allogeneic human umbilical cord derived mesenchymal stromal cells (hCT-MSCs) have potential therapeutic benefits in these critically ill patients, but feasibility and safety data are lacking.

Materials And Methods: In this phase I multisite study, 10 patients with COVID-19-related ARDS were treated with 3 daily intravenous infusions of hCT-MSCs (1 million cells/kg, maximum dose 100 million cells).

The association between social determinants of health and psychological distress during the COVID-19 pandemic: a secondary analysis among four racial/ethnic groups.

Background: Racial disparities in psychological distress associated with COVID-19 remain unclear in the U.S. This study aims to investigate the associations between social determinants of health and COVID-19-related psychological distress across different racial/ethnic groups in the US (i.

Nurse Faculty Provide Essential Support to Graduate Nursing Students During COVID-19 Pandemic.

Nurses in formal and informal leadership roles have been stretched to fulfill duties in their own role and be pulled into staffing. These emerging leaders have little energy to pursue an advanced academic degree when they are already considering leaving the profession. In a health care industry filled with ambiguity and volatility, continued efforts to support, retain, and recruit nurses in graduate leadership programs are essential.

Longitudinal associations between cancer history and cognitive functioning among older adults.

Objectives: This study aimed to examine (1) whether cancer history accelerates older adults' rates of cognitive decline over time and (2) whether chemotherapy increases older cancer patients'/ survivors' rates of cognitive decline over time.

Methods: This longitudinal study drew a subsample of 8811 adults aged 65 or older from Wave 6 of the Health and Retirement Study in 2002 and followed biennually until Wave 13 in 2016. Linear mixed-effects models were performed to test whether cancer history and chemotherapy were associated with accelerated rates of cognitive decline over time among older adults in different age groups.

Parenting, privilege, and pandemic: From surviving to thriving as a mother in the academy.

As women who have dual roles as parents and academicians, COVID-19 has presented new challenges and opportunities that have impacted our personal and professional lives. This essay provides insight into unique obstacles from the perspective of mothers, researchers, and social workers and challenges the traditional models of work/life balance as professionals in academics. This reflexive essay provides the narratives and experiences of one assistant professor and two doctoral students who are learning to navigate motherhood and professional responsibilities amidst a global pandemic.

T cell-depleted cultured pediatric thymus tissue as a model for some aspects of human age-related thymus involution.

Human age-related thymus involution is characterized by loss of developing thymocytes and the thymic epithelial network that supports them, with replacement by adipose tissue. The mechanisms that drive these changes are difficult to study in vivo due to constant trafficking to and from the thymus. We hypothesized that the loss of thymocytes that occurs during human thymic organ cultures could model some aspects of thymus involution and begin to identify mechanisms that drive age-related changes in the thymic microenvironment.

When falls become fatal-Clinical care sequence.

Objectives: This study encompassed fall-related deaths, including those who died prior to medical care, that were admitted to multiple healthcare institutions, regardless of whether they died at home, in long-term care, or in hospice. The common element was that all deaths resulted directly or indirectly from injuries sustained during a fall, regardless of the temporal relationship. This comprehensive approach provides an unusual illustration of the clinical sequence of fall-related deaths.

Histopathologic assessment of cultured human thymus.

The maintenance and propagation of complex mixtures of cells in vitro in the form of native organs or engineered organoids has contributed to understanding mechanisms of cell and organ development and function which can be translated into therapeutic benefits. For example, allogeneic cultured postnatal human thymus tissue has been shown to support production of naïve recipient T cells when transplanted into patients with complete DiGeorge anomaly and other genetic defects that result in congenital lack of a thymus. Patients receiving such transplants typically exhibit reversal of their immunodeficiency and normalization of their peripheral blood T cell receptor V-beta repertoire, with long-term survival.

Automated thawing increases recovery of colony-forming units from banked cord blood unit grafts.

Background: The cell dose infused for cord blood transplantation strongly correlates with outcomes following transplantation. Post thaw recoveries can be improved by washing cord blood units (CBUs) in dextran/albumin. Early methods used a labor-intensive manual process.

Systems theory as a framework for examining a college campus-based support program for the former foster youth.

Increased attention to former foster youth pursuing post-secondary education has resulted in the creation of college campus based support programs to address their need. However, limited empirical evidence and theoretical knowledge exist about these programs. This study seeks to describe the application of systems theory as a framework for examining a college campus based support program for former foster youth.

The Curvilinear Relationship Between Attitude Certainty and Attitudinal Advocacy.

Do people advocate more on behalf of their own attitudes and opinions when they feel certain or uncertain? Although considerable past research suggests that people are more likely to advocate when they feel highly certain, there also is evidence for the opposite effect-that people sometimes advocate more when they experience a loss of certainty. The current research seeks to merge these insights. Specifically, we explore the possibility that the relationship between attitude certainty and attitudinal advocacy is curvilinear.

Evaluation of Temporal Changes in Urine-based Metabolomic and Kidney Injury Markers to Detect Compound Induced Acute Kidney Tubular Toxicity in Beagle Dogs.

Urinary protein biomarkers and metabolomic markers have been leveraged to detect acute Drug Induced Kidney Injury (DIKI) in rats; however, the utility of these indicators to enable early detection of DIKI in canine models has not been well documented. Therefore, we evaluated temporal changes in biomarkers and metabolites in urine from male and female beagle dogs. Gentamicin- induced kidney lesions in male dogs were characterized by moderate to severe tubular epithelial cell degeneration/necrosis, epithelial cell regeneration and dilation; and a unique urinebased metabolomic fingerprint.

Development and validation of a rapid, aldehyde dehydrogenase bright-based cord blood potency assay.

Banked, unrelated umbilical cord blood provides access to hematopoietic stem cell transplantation for patients lacking matched bone marrow donors, yet 10% to 15% of patients experience graft failure or delayed engraftment. This may be due, at least in part, to inadequate potency of the selected cord blood unit (CBU). CBU potency is typically assessed before cryopreservation, neglecting changes in potency occurring during freezing and thawing.

Attitude Certainty and Attitudinal Advocacy: The Unique Roles of Clarity and Correctness.

When and why do people advocate on behalf of their attitudes? Past research suggests that attitude certainty is one important determinant. The current research seeks to provide more nuanced insight into this relationship by (a) exploring the unique roles of attitude clarity and attitude correctness, and (b) mapping clarity and correctness onto different forms of advocacy (sharing intentions and persuasion intentions). Across four studies, we find that correctness but not clarity plays an important role in promoting persuasion intentions, whereas both correctness and clarity help shape sharing intentions.

Early prediction of polymyxin-induced nephrotoxicity with next-generation urinary kidney injury biomarkers.

Despite six decades of clinical experience with the polymyxin class of antibiotics, their dose-limiting nephrotoxicity remains difficult to predict due to a paucity of sensitive biomarkers. Here, we evaluate the performance of standard of care and next-generation biomarkers of renal injury in the detection and monitoring of polymyxin-induced acute kidney injury in male Han Wistar rats using colistin (polymyxin E) and a polymyxin B (PMB) derivative with reduced nephrotoxicity, PMB nonapeptide (PMBN). This study provides the first histopathological and biomarker analysis of PMBN, an important test of the hypothesis that fatty acid modifications and charge reductions in polymyxins can reduce their nephrotoxicity.

An acute rat in vivo screening model to predict compounds that alter blood glucose and/or insulin regulation.

Introduction: Drug-induced glucose dysregulation and insulin resistance have been associated with weight gain and potential induction and/or exacerbation of diabetes mellitus in the clinic suggesting they may be safety biomarkers when developing antipsychotics. Glucose and insulin have also been suggested as potential efficacy biomarkers for some oncology compounds. The objective of this study was to qualify a medium throughput rat in vivo acute Intravenous Glucose Tolerance Test (IVGTT) for predicting compounds that will induce altered blood glucose and/or insulin levels.

Effect of ghrelin and anamorelin (ONO-7643), a selective ghrelin receptor agonist, on tumor growth in a lung cancer mouse xenograft model.

Purpose: Anamorelin (ONO-7643) is an orally active ghrelin receptor agonist in development for non-small cell lung cancer (NSCLC)-related anorexia/cachexia. It displays both orexigenic and anabolic properties via ghrelin mimetic activity and transient increases in growth hormone (GH). However, increasing GH and insulin-like growth factor-1 in cancer patients raises concerns of potentially stimulating tumor growth.

Regulatory and reimbursement innovation.

Coverage with evidence development and parallel review for molecular diagnostics aid regulation and reimbursement.

Renal biomarker changes associated with hyaline droplet nephropathy in rats are time and potentially compound dependent.

Alpha 2u-globulin mediated hyaline droplet nephropathy (HDN) is a male rat specific lesion induced when a compound or metabolite binds to alpha 2u-globulin. The objective of this study was to investigate if the newer and more sensitive renal biomarkers would be altered with HDN as well as be able to distinguish between HDN and oxidative stress-induced kidney injury. Rats were dosed orally for 7 days to determine (1) if HDN (induced by 2-propanol or D-limonene) altered the newer renal biomarkers and not BUN or creatinine, (2) if renal biomarkers could distinguish between HDN and oxidative stress-induced kidney injury (induced by potassium bromate), (3) sensitivity of HDN-induced renal biomarker changes relative to D-limonene dose, and (4) reversibility of HDN and renal biomarkers, using vehicle or 300 mg/kg/day D-limonene with 7 days of dosing and necropsies scheduled over the period of Days 8-85.

Effects of Internet use on well-being among adults with physical disabilities: a review.

Purpose: The current review provides a summarized synthesis and evaluation of studies addressing the effects of Internet use on well-being among adults (19-64 years old) with physical disabilities.

Methods: Potential studies were identified through search of electronic bibliographic databases. Outcome studies were chosen for initial review if the study (1) involved a randomized controlled trial, a quasi-experimental, or a pre-experimental design, (2) appeared in the English language, (3) was published in a scholarly journal, and (4) was published before April, 2011.

Optional inferior vena cava filter retrieval with retained thrombus: an in vitro model.

Purpose: Retrieval of an optional inferior vena cava (IVC) filter with retained thrombus may result in pulmonary emboli if the trapped thrombus is not removed along with the filter. An in vitro model was developed to determine the fate of trapped thrombus during filter removal.

Materials And Methods: An in vitro IVC flow model was created with 25-mm inner diameter tubing and a 50% glycerol/water solution.

Discovery of highly selective inhibitors of p38alpha.

The p38 MAP kinases are a family of serine/threonine protein kinases that play a key role in cellular pathways leading to pro-inflammatory responses. We have developed and implemented a method for rapidly identifying and optimizing potent and selective p38alpha inhibitors, which is amenable to other targets and target classes. A diverse library of druggable, purified and quantitated molecules was assembled and standardized enzymatic assays were performed in a microfluidic format that provided very accurate and precise inhibition data allowing for development of SAR directly from the primary HTS.