Drug Screening Using Normal Cell and Cancer Cell Mixture in an Automated 3D Cell Culture System.

Three-dimensional (3D) cell culture creates a more physiologically relevant environment for enhanced drug screening capabilities using microcarriers. An automated 3D system that integrates robotic manipulators, liquid handling systems, sensors, and environment control systems has the capacity to handle multiple samples in parallel, perform repetitive tasks, and provide real-time monitoring and analysis. This chapter describes a potential 3D cell culture drug screening model by combining renal proximal tubule cells as a representative normal cell line with cancer cell lines.

Toward a new clinical pragmatism: method in clinical ethics consultation.

In this paper, I leverage the pragmatist tradition in philosophy, the collective wisdom of scholarship in clinical ethics consultation, and earlier attempts to apply pragmatism in clinical ethics to develop a new vision of clinical ethics practice called New Clinical Pragmatism. It argues that clinical ethics methodology, from the New Clinical Pragmatist's perspective, amounts to the recommendation that consultants should customize a methodological approach, drawing on the various available methods, depending on the demands of the specific case, and should avoid attempts to identify a 'true' methodology but to the incoherence and inevitable failure of those attempts. I argue that pragmatism's emphasis on practical wisdom and experimentation allow the New Clinical Pragmatist to do this while avoiding irrationality in choosing methods.

Renal autocrine neuropeptide FF (NPFF) signaling regulates blood pressure.

The kidney and brain play critical roles in the regulation of blood pressure. Neuropeptide FF (NPFF), originally isolated from the bovine brain, has been suggested to contribute to the pathogenesis of hypertension. However, the roles of NPFF and its receptors, NPFF-R1 and NPFF-R2, in the regulation of blood pressure, via the kidney, are not known.

Caveolin-1, a Determinant of the Fate of MCF-7 Breast Cancer Cells.

Background: The scaffolding protein, caveolin-1 (Cav-1), participates in multiple cellular functions including promotion of sodium excretion from the kidney. Loss of expression of Cav-1 is associated with tumorigenesis of various types of cancer. We have shown the potential link between hypertension and breast cancer via abnormal function of the G protein-coupled receptor kinase type 4 (GRK4).

Bridging the gaps in newborn screening programmes: Challenges and opportunities to detect haemoglobinopathies in Africa.

Background: Haemoglobinopathies, including sickle cell disease and β-thalassaemia, are monogenic disorders with a relatively higher prevalence among malaria-endemic areas in Africa. Despite this prevalence, most African countries lack the necessary resources for diagnosing and managing these debilitating conditions.

Aim: This study provides a critical review of newborn screening for detecting haemoglobinopathies in Africa, highlighting challenges and proposing strategies for improved diagnosis and management.

Transient depletion of macrophages alters local inflammatory response at the site of disc herniation in a transgenic mouse model.

Objective: Macrophages are abundantly detected at sites of disc herniation, however, their function in the disease progression is unclear. We aim to investigate the functions of macrophages in acute disc herniation using a macrophage Fas-induced apoptosis (MaFIA) transgenic mouse strain.

Method: To transiently deplete macrophages, a dimerizer, AP20187, or vehicle solution was administered via intraperitoneal injection to MaFIA mice immediately, day 1 and 2 after annular puncture induced disc herniation.

Reducing brain TACE activity improves neuroinflammation and cardiac function in heart failure rats.

Tumor necrosis factor (TNF)-α converting enzyme (TACE) is a key metalloprotease mediating ectodomain shedding of a variety of inflammatory mediators, substrates, and growth factors. We previously reported that TACE-mediated production of TNF-α in the hypothalamic paraventricular nucleus (PVN) contributes to sympathetic excitation in heart failure (HF). Here, we sought to determine whether central interventions in TACE activity attenuate neuroinflammation and improve cardiac function in heart failure.

Peroxiredoxin-4 and Dopamine D5 Receptor Interact to Reduce Oxidative Stress and Inflammation in the Kidney.

Reactive oxygen species are highly reactive molecules generated in different subcellular compartments. Both the dopamine D5 receptor (DR) and endoplasmic reticulum (ER)-resident peroxiredoxin-4 (PRDX4) play protective roles against oxidative stress. This study is aimed at investigating the interaction between PRDX4 and DR in regulating oxidative stress in the kidney.

Inverse Salt Sensitivity of Blood Pressure Is Associated with an Increased Renin-Angiotensin System Activity.

High and low sodium diets are associated with increased blood pressure and cardiovascular morbidity and mortality. The paradoxical response of elevated BP in low salt diets, aka inverse salt sensitivity (ISS), is an understudied vulnerable 11% of the adult population with yet undiscovered etiology. A linear relationship between the number of single nucleotide polymorphisms (SNPs) in the dopamine D receptor ( rs6276 and 6277), and the sodium myo-inositol cotransporter 2 (, rs11074656), as well as decreased expression of these two genes in urine-derived renal proximal tubule cells (uRPTCs) isolated from clinical study participants suggest involvement of these cells in ISS.

Inverse Salt Sensitivity of Blood Pressure: Mechanisms and Potential Relevance for Prevention of Cardiovascular Disease.

Purpose Of Review: To review the etiology of inverse salt sensitivity of blood pressure (BP).

Recent Findings: Both high and low sodium (Na) intake can be associated with increased BP and cardiovascular morbidity and mortality. However, little is known regarding the mechanisms involved in the increase in BP in response to low Na intake, a condition termed inverse salt sensitivity of BP, which affects approximately 15% of the adult population.

Epithelial Sodium Channel Alpha Subunit (αENaC) Is Associated with Inverse Salt Sensitivity of Blood Pressure.

Salt sensitivity of blood pressure (BP) refers to an increase in BP following an increase in dietary salt, which is associated with increased incidence of cardiovascular disease and early death. However, decreased sodium intake also increases mortality and morbidity. Inverse salt sensitivity (ISS), defined as a paradoxical increase in BP on a low-salt diet, about 11% of the population, may be the cause of this phenomenon.

Amine Functionalized Trimetallic Nitride Endohedral Fullerenes: A Class of Nanoparticle to Tackle Low Back/Leg Pain.

Low back pain is the most common health problem with a prevalence of over 80% worldwide and an estimated annual cost of $100 billion in the United States. Intervertebral disc degeneration accounts for a major cause of low back pain. However, there is still a lack of safe and effective treatment to tackle this devastating condition.

Angiotensin II inhibits the A-type K current of hypothalamic paraventricular nucleus neurons in rats with heart failure: role of MAPK-ERK1/2 signaling.

Angiotensin II (ANG II)-mediated sympathohumoral activation constitutes a pathophysiological mechanism in heart failure (HF). Although the hypothalamic paraventricular nucleus (PVN) is a major site mediating ANG II effects in HF, the precise mechanisms by which ANG II influences sympathohumoral outflow from the PVN remain unknown. ANG II activates the ubiquitous intracellular MAPK signaling cascades, and recent studies revealed a key role for ERK1/2 MAPK signaling in ANG II-mediated sympathoexcitation in HF rats.

GRK4, A Potential Link between Hypertension and Breast Cancer.

Hypertension and breast cancer are two common diseases occurring in women. Clinical studies have shown increased breast cancer incidence in hypertensive women. Several lines of evidence demonstrate that G protein-coupled Receptor Kinase 4 (GRK4) could be a common risk factor for hypertension and breast cancer.

Transforming Growth Factor-α Acts in Hypothalamic Paraventricular Nucleus to Upregulate ERK1/2 Signaling and Expression of Sympathoexcitatory Mediators in Heart Failure Rats.

Activation of epidermal growth factor receptor (EGFR) tyrosine kinase is associated with increased extracellular signal-regulated kinase (ERK) 1/2 signaling in the hypothalamic paraventricular nucleus (PVN), which contributes to the sympathetic excitation in heart failure (HF). Transforming growth factor (TGF)-α is a major endogenous ligand for EGFR. The present study sought to determine whether TGF-α increases in the PVN in HF and promotes the activation of EGFR to increase ERK1/2 activity.

Maternal Angiotensin II-Induced Hypertension Sensitizes Postweaning High-Fat Diet-Elicited Hypertensive Response Through Increased Brain Reactivity in Rat Offspring.

Background Prenatal and postnatal insults can induce a physiological state that leaves offspring later in life vulnerable to subsequent challenges (stressors) eliciting cardiometabolic diseases including hypertension. In this study, we investigated whether maternal angiotensin II-induced hypertension in rats sensitizes postweaning high-fat diet (HFD)-elicited hypertensive response and whether this is associated with autonomic dysfunction and altered central mechanisms controlling sympathetic tone in offspring. Methods and Results When eating a low-lard-fat diet, basal mean arterial pressure of male offspring of normotensive or hypertensive dams were comparable.

The Hypertension Related Gene G-Protein Coupled Receptor Kinase 4 Contributes to Breast Cancer Proliferation.

Purpose: Clinical studies have shown that breast cancer risk is increased in hypertensive women. The underlying molecular mechanism remains undetermined. The current study tests our hypothesis that G protein coupled receptor kinase 4 (GRK4) is a molecule that links hypertension and breast cancer.

Coming to Terms with the Black Box Problem: How to Justify AI Systems in Health Care.

The use of opaque, uninterpretable artificial intelligence systems in health care can be medically beneficial, but it is often viewed as potentially morally problematic on account of this opacity-because the systems are black boxes. Alex John London has recently argued that opacity is not generally problematic, given that many standard therapies are explanatorily opaque and that we can rely on statistical validation of the systems in deciding whether to implement them. But is statistical validation sufficient to justify implementation of these AI systems in health care, or is it merely one of the necessary criteria? I argue that accountability, which holds an important role in preserving the patient-physician trust that allows the institution of medicine to function, contributes further to an account of AI system justification.

Dopamine D receptor-mediated decreases in mitochondrial reactive oxygen species production are cAMP and autophagy dependent.

Overproduction of reactive oxygen species (ROS) plays an important role in the pathogenesis of hypertension. The dopamine D receptor (DR) is known to decrease ROS production, but the mechanism is not completely understood. In HEK293 cells overexpressing DR, fenoldopam, an agonist of the two D-like receptors, DR and DR, decreased the production of mitochondria-derived ROS (mito-ROS).

SNX-PXA-RGS-PXC Subfamily of SNXs in the Regulation of Receptor-Mediated Signaling and Membrane Trafficking.

The SNX-PXA-RGS-PXC subfamily of sorting nexins (SNXs) belongs to the superfamily of SNX proteins. SNXs are characterized by the presence of a common phox-homology (PX) domain, along with other functional domains that play versatile roles in cellular signaling and membrane trafficking. In addition to the PX domain, the SNX-PXA-RGS-PXC subfamily, except for SNX19, contains a unique RGS (regulators of G protein signaling) domain that serves as GTPase activating proteins (GAPs), which accelerates GTP hydrolysis on the G protein α subunit, resulting in termination of G protein-coupled receptor (GPCR) signaling.

Preclinical efficacy of ribavirin in SHH and group 3 medulloblastoma.

Objective: Medulloblastoma, the most common pediatric brain malignancy, has Sonic Hedgehog (SHH) and group 3 (Myc driven) subtypes that are associated with the activity of eukaryotic initiation factor 4E (eIF4E), a critical mediator of translation, and enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and master regulator of transcription. Recent drug repurposing efforts in multiple solid and hematologic malignancies have demonstrated that eIF4E and EZH2 are both pharmacologically inhibited by the FDA-approved antiviral drug ribavirin. Given the molecular overlap between medulloblastoma biology and known ribavirin activity, the authors investigated the preclinical efficacy of repurposing ribavirin as a targeted therapeutic in cell and animal models of medulloblastoma.