Second-Order Effects of Chemotherapy Pharmacodynamics and Pharmacokinetics on Tumor Regression and Cachexia.

Drug dose response curves are ubiquitous in cancer biology, but these curves are often used to measure differential response in first-order effects: the effectiveness of increasing the cumulative dose delivered. In contrast, second-order effects (the variance of drug dose) are often ignored. Knowledge of second-order effects may improve the design of chemotherapy scheduling protocols, leading to improvements in tumor response without changing the total dose delivered. By considering treatment schedules with identical cumulative dose delivered, we characterize differential treatment outcomes resulting from high variance schedules (e.g. high dose, low dose) and low variance schedules (constant dose). We extend a previous framework used to quantify second-order effects, known as antifragility theory, to investigate the role of drug pharmacokinetics. Using a simple one-compartment model, we find that high variance schedules are effective for a wide range of cumulative dose values. Next, using a mouse-parameterized two-compartment model of 5-fluorouracil, we show that schedule viability depends on initial tumor volume. Finally, we illustrate the trade-off between tumor response and lean mass preservation. Mathematical modeling indicates that high variance dose schedules provide a potential path forward in mitigating the risk of chemotherapy-associated cachexia by preserving lean mass without sacrificing tumor response.

GPR19 Coordinates Multiple Molecular Aspects of Stress Responses Associated with the Aging Process.

G protein-coupled receptors (GPCRs) play a significant role in controlling biological paradigms such as aging and aging-related disease. We have previously identified receptor signaling systems that are specifically associated with controlling molecular pathologies associated with the aging process. Here, we have identified a pseudo-orphan GPCR, G protein-coupled receptor 19 (GPR19), that is sensitive to many molecular aspects of the aging process. Through an in-depth molecular investigation process that involved proteomic, molecular biological, and advanced informatic experimentation, this study found that the functionality of GPR19 is specifically linked to sensory, protective, and remedial signaling systems associated with aging-related pathology. This study suggests that the activity of this receptor may play a role in mitigating the effects of aging-related pathology by promoting protective and remedial signaling systems. GPR19 expression variation demonstrates variability in the molecular activity in this larger process. At low expression levels in HEK293 cells, GPR19 expression regulates signaling paradigms linked with stress responses and metabolic responses to these. At higher expression levels, GPR19 expression co-regulates systems involved in sensing and repairing DNA damage, while at the highest levels of GPR19 expression, a functional link to processes of cellular senescence is seen. In this manner, GPR19 may function as a coordinator of aging-associated metabolic dysfunction, stress response, DNA integrity management, and eventual senescence.

Development of Partial Tolerance to the Suppressing Effect of the Positive Allosteric Modulator of the GABAB Receptor, KK-92A, on Alcohol Self-Administration in Rats.

AIMS: A recent study reported how acute treatment with KK-92A, a newly synthesized positive allosteric modulator (PAMs) of the GABAB receptor (GABAB PAMs), suppressed a series of alcohol-related behaviors, including operant oral alcohol self-administration, in selectively bred Sardinian alcohol-preferring (sP) rats. These findings lead to the addition of KK-92A to the long list of GABAB PAMs capable of reducing, after acute treatment, alcohol self-administration in rats. As a further step toward a more complete characterization of the anti-addictive properties of KK-92A, the present study was designed to assess the effect of repeated treatment with the compound on alcohol self-administration. METHODS: sP rats were trained to lever-respond for oral alcohol (15%, v/v) under the fixed ratio 5 (FR5) schedule of reinforcement. Once lever-responding behavior had stabilized, KK-92A (0, 5, 10 and 20 mg/kg, i.p.) was administered 30 min prior to 10 consecutive daily self-administration sessions (likewise occurring under the FR5 schedule). RESULTS: The first injection of KK-92A produced a dose-related suppression in number of lever-responses for alcohol and amount of self-administered alcohol. Magnitude of the suppressing effect of KK-92A decreased over the following two self-administration sessions and then tended to stabilize on continuation of treatment. Statistical significance at post hoc analysis was maintained only by the highest dose tested (20 mg/kg). CONCLUSIONS: These data suggest the development of partial tolerance to the reducing effect of repeatedly administered KK-92A on alcohol self-administration. The agonistic component of the ago-allosteric profile of KK-92A is discussed as the likely key element underlying the observed tolerance.

Structural basis for auxiliary subunit KCTD16 regulation of the GABAB receptor.

Metabotropic GABAB receptors mediate a significant fraction of inhibitory neurotransmission in the brain. Native GABAB receptor complexes contain the principal subunits GABAB1 and GABAB2, which form an obligate heterodimer, and auxiliary subunits, known as potassium channel tetramerization domain-containing proteins (KCTDs). KCTDs interact with GABAB receptors and modify the kinetics of GABAB receptor signaling. Little is known about the molecular mechanism governing the direct association and functional coupling of GABAB receptors with these auxiliary proteins. Here, we describe the high-resolution structure of the KCTD16 oligomerization domain in complex with part of the GABAB2 receptor. A single GABAB2 C-terminal peptide is bound to the interior of an open pentamer formed by the oligomerization domain of five KCTD16 subunits. Mutation of specific amino acids identified in the structure of the GABAB2-KCTD16 interface disrupted both the biochemical association and functional modulation of GABAB receptors and G protein-activated inwardly rectifying K+ channel (GIRK) channels. These interfacial residues are conserved among KCTDs, suggesting a common mode of KCTD interaction with GABAB receptors. Defining the binding interface of GABAB receptor and KCTD reveals a potential regulatory site for modulating GABAB-receptor function in the brain.

Inhibition of the Monocarboxylate Transporter 1 (MCT1) Promotes 3T3-L1 Adipocyte Proliferation and Enhances Insulin Sensitivity.

Enlarged, hypertrophic adipocytes are less responsive to insulin and are a hallmark feature of obesity, contributing to many of the negative metabolic consequences of excess adipose tissue. Although the mechanisms remain unclear, the adipocyte size appears to be inversely correlated with insulin sensitivity and glucose tolerance, wherein smaller adipocytes are insulin-sensitive and larger adipocytes develop insulin resistance and exhibit an impaired glucose uptake. Thus, pharmacological strategies aimed at regulating adipocyte hypertrophy (increase in adipocyte size) in favor of promoting hyperplasia (increase in adipocyte number) have the potential to improve adipocyte insulin sensitivity and provide therapeutic benefits in the context of metabolic disorders. As white adipose tissue can metabolize large amounts of glucose to lactate, using transcriptomics and in vitro characterization we explore the functional consequences of inhibiting monocarboxylate transporter 1 (MCT1) activity in fully differentiated adipocytes. Our studies show that the pharmacological inhibition of MCT1, a key regulator of the cellular metabolism and proliferation, promotes the re-entry of mature adipocytes into the cell cycle. Furthermore, we demonstrate that inhibitor-treated adipocytes exhibit an enhanced insulin-stimulated glucose uptake as compared with untreated adipocytes, and that this outcome is dependent on the cyclin-dependent kinase 1 (CDK1) activity. In summary, we identify a mechanism though which MCT1 inhibition improves the insulin sensitivity of mature adipocytes by inducing cell cycle re-entry. These results provide the foundation for future studies investigating the role MCT1 plays in adipocyte hyperplasia, and its therapeutic potential as a drug target for obesity and metabolic disease.

Intersection of the Orphan G Protein-Coupled Receptor, GPR19, with the Aging Process.

G protein-coupled receptors (GPCRs) represent one of the most functionally diverse classes of transmembrane proteins. GPCRs and their associated signaling systems have been linked to nearly every physiological process. They also constitute nearly 40% of the current pharmacopeia as direct targets of remedial therapies. Hence, their place as a functional nexus in the interface between physiological and pathophysiological processes suggests that GPCRs may play a central role in the generation of nearly all types of human disease. Perhaps one mechanism through which GPCRs can mediate this pivotal function is through the control of the molecular aging process. It is now appreciated that, indeed, many human disorders/diseases are induced by GPCR signaling processes linked to pathological aging. Here we discuss one such novel member of the GPCR family, GPR19, that may represent an important new target for novel remedial strategies for the aging process. The molecular signaling pathways (metabolic control, circadian rhythm regulation and stress responsiveness) associated with this recently characterized receptor suggest an important role in aging-related disease etiology.

Giving while grieving: Racism-related stress and psychological resilience in Black/African American registered nurses.

BACKGROUND: Studies have found race-related stress psychologically and physiologically harms members of stigmatized racial groups. However, the stressor is racism, not race. PURPOSE: This study examined the relationship between racism-related stress and psychological resilience in Black/African American nurses. METHOD: This study used a cross-sectional, quantitative, correlational design with two instruments, an investigator-developed demographic questionnaire and a convenience sample. FINDINGS: Participants perceived they have low psychological resilience in stressful situations. With racism-related stress, in particular, participants perceived they are affected by both lived and vicarious racism - ruminating over past occurrences, and expecting/worrying that racism will happen to them or other Black/African American people. There was a significant positive correlation between participants' perceived psychological resilience, their ability to assess the nature of the racism-related stressor and their ability to mitigate its harmful effects by identifying and utilizing their coping resources. There was a negative correlation between racism-related stress and psychological resilience. DISCUSSION: There is a need for continued research on racism-related stress among Black/African American nurses. Further, healthcare organizations, advisably through their diversity, equity and inclusion (DEI) programs, must develop systemic approaches to meeting the unique needs of the Black/African American workforce.

O-GlcNAc Engineering of GPCR Peptide-Agonists Improves Their Stability and in Vivo Activity.

Peptide agonists of GPCRs and other receptors are powerful signaling molecules with high potential as biological tools and therapeutics, but they are typically plagued by instability and short half-lives in vivo. Nature uses protein glycosylation to increase the serum stability of secreted proteins. However, these extracellular modifications are complex and heterogeneous in structure, making them an impractical solution. In contrast, intracellular proteins are subjected to a simple version of glycosylation termed O-GlcNAc modification. In our studies of this modification, we found that O-GlcNAcylation inhibits proteolysis, and strikingly, this stabilization occurs despite large distances in primary sequence (10-15 amino acids) between the O-GlcNAc and the site of cleavage. We therefore hypothesized that this "remote stabilization" concept could be useful to engineer the stability and potentially additional properties of peptide or protein therapeutics. Here, we describe the application of O-GlcNAcylation to two clinically important peptides: glucagon-like peptide-1 (GLP-1) and the parathyroid hormone (PTH), which respectively help control glucose and calcium levels in the blood. For both peptides, we found O-GlcNAcylated analogs that are equipotent to unmodified peptide in cell-based activation assays, while several GLP-1 analogs were biased agonists relative to GLP-1. As we predicted, O-GlcNAcylation can improve the stability of both GLP-1 and PTH in serum despite the fact that the O-GlcNAc can be quite remote from characterized sites of peptide cleavage. The O-GlcNAcylated GLP-1 and PTH also displayed significantly improved in vivo activity. Finally, we employed structure-based molecular modeling and receptor mutagenesis to predict how O-GlcNAcylation can be accommodated by the receptors and the potential interactions that contribute to peptide activity. This approach demonstrates the potential of O-GlcNAcylation for generating analogs of therapeutic peptides with enhanced proteolytic stability.

A Novel Mentoring Program for Inner-City Middle and High School Students.

This article discusses the Provost Scholars, a novel University five-year Mentoring Program for middle and high school students in an inner-city school district. The Provost Scholars is an innovative enrichment Program in which a partnership was formed between an under-resourced inner city school district and a private research university in Cleveland, Ohio. The Program was formed to help students graduate from high school. As these students experience success and empowerment, their willingness and ability to give back to the health of the community is enhanced. The primary goal of the Provost Scholars Mentoring Program is to prepare students for entry into and graduation from colleges/universities, technical/vocational schools, or to find a successful place in the workforce. This article describes a number of initiatives established to ensure the success of the Scholars. One key aspect of the Programs' success is a strong personal interest, caring, engagement, and partnership between the administrative staffs of the following two educational institutions: Case Western Reserve University and the East Cleveland School District, as well as the committed relationships of the university Mentors and the Scholars. Students who participate in the Program are expected to demonstrate improved grades, higher ACT/SAT scores, and to meet the requirements for admission to the colleges and universities of their choice, or to develop skills for meaningful employment in industry.

Spiritual Needs of Older Adults in Long-Term Care: The Nurse's Role.

In this article we examine the nurse's role in assessing the spiritual needs of older adults in long-term care. The spiritual needs of older adults have not been adequately addressed in nursing care planning, and this has diminished the quality of care for residents in long-term care facilities. Understanding spirituality as a coping mechanism or social support intervention for older adults would be helpful to nurses who provide care to geriatric residents. Based on the literature, several topics of significance are discussed, including definitions of spirituality and religion, cultural considerations, research on spirituality as a coping mechanism and social support intervention, spiritual assessment models, and nurses' use of spirituality and religion in planning holistic care for long-term residents.

Beauty for Ashes: A Church-Based Diabetes Care Program.

The pilot study described here was a test of interventions designed to enhance long-term disease management of African-Americans with type 2 diabetes in faith-based organizations. A quasi-experimental design based on 46 participants was used comparing three interventions: guided imagery, group counseling, and routine care. Unexpectedly, the number of self-reported hypoglycemic episodes significantly increased in the Rational Emotive Behavioral Therapy (REBT) group, depressive symptoms significantly increased in the guided imagery group, and the mean hemoglobin A1c values did not significantly differ for any group. In future research, the authors will incorporate an interim step investigating the theory of integration (Hernandez, Antone, & Cornelius, 1999) to increase the explanatory power in assessing treatment effects of African-Americans in faith-based organizations.

A Church-Based Diabetes Care Survey in St. Thomas, U.S. Virgin Islands.

Forty-eight (N = 48) African-Caribbeans participated in a church-based diabetes care survey in St. Thomas, U.S. Virgin Islands. The purpose of this pilot study was to determine whether integration was a significant predictor of depressive symptoms and glycemic control in persons with type 2 diabetes among African-Caribbeans in faith-based organizations (FBO), controlling for demographic variables. Data were collected on measures of integration of diabetes, acceptance, depressive symptoms, number of hypoglycemic episodes, hemoglobin Alc, and demographic characteristics. The majority of subjects were female. Acceptance and depression were negatively correlated, and acceptance and integration were positively correlated. Depression and number of mild hypoglycemic episodes were also positively correlated. Surprisingly, integration was not significantly related to hemoglobin Alc, number of hypoglycemic episodes, and depressive symptoms. Implications of these findings are presented.

The Employer-Led Health Care Revolution.

To tame its soaring health care costs, intel tried many popular approaches: "consumer-driven health care" offerings such as high-deductible/low-premium plans, on-site clinics and employee wellness programs. But by 2009 intel realized that those programs alone would not enable the company to solve the problem, because they didn't affect its root cause: the steadily rising cost of the care employees and their families were receiving. Intel projected that its health care expenditures would hit a whopping $1 billion by 2012. So the company decided to try a novel approach. As a large purchaser of health services and with expertise in quality improvement and supplier management, intel was uniquely positioned to drive transformation in its local health care market. The company decided that it would manage the quality and cost of its health care suppliers with the same rigor it applied to its equipment suppliers by monitoring quality and cost. It spearheaded a collaborative effort in Portland, Oregon, that included two health systems, a plan administrator, and a major government employer. So far the Portland collaborative has reduced treatment costs for certain medical conditions by 24% to 49%, improved patient satisfaction, and eliminated over 10,000 hours worth of waste in the two health systems' business processes.

Stress-induced nuclear import of apoptosis signal-regulating kinase 1 is mediated by karyopherin α2/ß1 heterodimer.

The apoptosis signal-regulating kinase 1 (ASK1) is activated in response to a wide variety of extracellular stressors. Consequently, dysregulation of ASK1 is associated with multiple pathologies. Here, we show that ASK1 translocates from the cytoplasm to the nucleus in HEK293 cells and human cardiomyocytes in response to hydrogen peroxide (H(2)O(2)) or angiotensin respectively. Immunoprecipitation and mass spectrometry experiments reveal that ASK1 physically interacts with the karyopherin α2/ß1 heterodimer in response to stress and genetic knockdown experiments confirm that this association mediates H(2)O(2)-induced ASK1 nuclear translocation. In addition, we have identified a nuclear localization signal (NLS)-like motif within the primary amino acid sequence of ASK1 composed of two clusters of basic amino acids separated by an intervening 16 amino acid spacer, KR[ACANDLLVDEFLKVSS]KKKK. Mutation of the downstream lysine cluster markedly reduces the H(2)O(2)-induced ASK1-karyopherin α2/ß1 interaction and inhibits ASK1 nuclear translocation. Furthermore, we demonstrate that nuclear ASK1 is active and participates in H(2)O(2)-induced ASK1-mediated cell death. Collectively, our findings have identified a functional interaction between ASK1 and the karyopherin α2/ß1 heterodimer and have also revealed a novel mechanism by which nuclear trafficking regulates the apoptotic function of ASK1 in response to stress.

The discovery of indole full agonists of the neurotensin receptor 1 (NTSR1).

Neurotensin (NT) is an endogenous tridecapeptide found in the central nervous system (CNS) and in peripheral tissues. Neurotensin exerts a wide range of physiological effects and it has been found to play a critical role in a number of human diseases, such as schizophrenia, Parkinson's disease and drug addiction. The discovery of small-molecule non-peptide neurotensin receptor (NTSR) modulators would represent an important breakthrough as such compounds could be used as pharmacological tools, to further decipher the cellular functions of neurotensin, and potentially as therapeutic agents to treat human disease. Herein, we report the identification of non-peptide low-micromolar neurotensin receptor 1 (NTSR1) full agonists, discovered through structural optimization of the known NTSR1 partial agonist 1. In vitro cellular screenings, based on an intracellular Ca(2+) mobilization assay, revealed our best hit molecule 8 (SR-12062) to have an EC50 of 2 µM at NTSR1 with full agonist behaviour (Emax=100%), showing a higher efficacy and ∼90-fold potency improvement compared to parent compound 1 (EC50=178 µM; Emax=17%).

Characteristics of smokers with type 2 diabetes.

AIM: The purpose of this secondary analysis was to identify the characteristics of smokers with type 2 diabetes, enrolled in a smoking cessation program. BACKGROUND: The health consequences of smoking are particularly severe for individuals with diabetes who smoke. METHODS: The characteristics of 227 smokers with type 2 diabetes were analyzed to determine which traits were more likely to be associated with quit success. RESULTS: Results of the data analysis indicate that smokers with type 2 diabetes were more likely to be abstinent 30 days and 6 months after the quit date if they attended a majority of the program classes and support groups; and used cessation medications. Expressing concerns about the expense of cigarettes was also associated with quit success at 6 months. CONCLUSIONS: Although studies have examined compliance with other diabetes care recommendations, few have evaluated the characteristics of individuals with diabetes who smoke.

Factors Associated with African-American Women's Decisions to Participate in Genetic Research.

The purpose of this study was to determine the factors that are associated with African-American (AA) women's decisions to participate in genetic research. Using a descriptive correlational design, a convenience sample of African-American women (age ≥ 40) was recruited from various locations in the Midwest. During semi-structured interviews, demographics, psychological factors, knowledge of and attitudes toward genetics were collected. Of the 98 women (mean age 53), 66% indicated that they were unwilling to participate, despite having positive attitudes. Correlations were found between genetic knowledge and attitudes toward genetics (r = .35, p = .001), and decision-making to participate and attitudes toward genetics (r = .40, p = .001). Data revealed decisions were largely associated with their lack of knowledge and resulting perceptions. Efforts should be made to inform African-American women about the benefits of the new science through planned, culturally specific, and sensitive interventions that incorporate genetic and health literacy programs.

Defining and Addressing Research Priorities in Cancer Cachexia through Transdisciplinary Collaboration.

For many patients, the cancer continuum includes a syndrome known as cancer-associated cachexia (CAC), which encompasses the unintended loss of body weight and muscle mass, and is often associated with fat loss, decreased appetite, lower tolerance and poorer response to treatment, poor quality of life, and reduced survival. Unfortunately, there are no effective therapeutic interventions to completely reverse cancer cachexia and no FDA-approved pharmacologic agents; hence, new approaches are urgently needed. In May of 2022, researchers and clinicians from Moffitt Cancer Center held an inaugural retreat on CAC that aimed to review the state of the science, identify knowledge gaps and research priorities, and foster transdisciplinary collaborative research projects. This review summarizes research priorities that emerged from the retreat, examples of ongoing collaborations, and opportunities to move science forward. The highest priorities identified include the need to (1) evaluate patient-reported outcome (PRO) measures obtained in clinical practice and assess their use in improving CAC-related outcomes; (2) identify biomarkers (imaging, molecular, and/or behavioral) and novel analytic approaches to accurately predict the early onset of CAC and its progression; and (3) develop and test interventions (pharmacologic, nutritional, exercise-based, and through mathematical modeling) to prevent CAC progression and improve associated symptoms and outcomes.

Delving into the reducing effects of the GABAB positive allosteric modulator, KK-92A, on alcohol-related behaviors in rats.

Recent studies have demonstrated the ability of the positive allosteric modulator (PAM) of the GABAB receptor (GABAB PAM), KK-92A, to suppress operant alcohol self-administration and reinstatement of alcohol seeking in selectively bred Sardinian alcohol-preferring (sP) rats. The present study was designed to scrutinize the suppressing effects of KK-92A on alcohol-related behaviors; to this end, four separate experiments were conducted to address just as many new research questions, some of which bear translational value. Experiment 1 found that 7-day treatment with KK-92A (0, 5, 10, and 20 mg/kg, intraperitoneally [i.p.]) effectively reduced alcohol intake in male sP rats exposed to the home-cage 2-bottle "alcohol (10% v/v) vs. water" choice regimen with 1 hour/day limited access, extending to excessive alcohol drinking the ability of KK-92A to suppress operant alcohol self-administration. Experiment 2 demonstrated that the ability of KK-92A to reduce lever-responding for alcohol was maintained also after acute, intragastric treatment (0, 20, and 40 mg/kg) in female sP rats trained to lever-respond for 15% (v/v) alcohol under the fixed ratio 5 schedule of reinforcement. In Experiment 3, acutely administered KK-92A (0, 5, 10, and 20 mg/kg, i.p.) dampened alcohol-seeking behavior in female sP rats exposed to a single session under the extinction responding schedule. Experiment 4 used a taste reactivity test to demonstrate that acute treatment with KK-92A (0 and 20 mg/kg, i.p.) did not alter either hedonic or aversive reactions to a 15% (v/v) alcohol solution in male sP rats, ruling out that KK-92A-induced reduction of alcohol drinking and self-administration could be due to alterations in alcohol palatability. Together, these results enhance the behavioral pharmacological profile of KK-92A and further strengthen the notion that GABAB PAMs may represent a novel class of ligands with therapeutic potential for treating alcohol use disorder.

Disubstituted piperidines as potent orexin (hypocretin) receptor antagonists.

A series of orexin receptor antagonists was synthesized based on a substituted piperidine scaffold. Through traditional medicinal chemistry structure-activity relationships (SAR), installation of various groups at the 3-6-positions of the piperidine led to modest enhancement in receptor selectivity. Compounds were profiled in vivo for plasma and brain levels in order to identify candidates suitable for efficacy in a model of drug addiction.