Notes

Matter option for well being technology review: A strategy merging multiple feature decisions and choice guidelines.
The recent development of modulators of cystic fibrosis transmembrane conductance regulator (CFTR) has allowed the life expectancy of cystic fibrosis patients to increase substantially resulting in more women with cystic fibrosis reaching child-bearing age. This however raises the issue of whether long-term use of CFTR modulators during pregnancy and breastfeeding is safe for the fetus and newborn, especially for their developing brain. A very limited number of case reports available so far has shown that the fetus or breastfed newborn is likely to be exposed to maternally administered CFTR modulators. Potential impacts of drug exposure on the developing brain are of particular importance as the consequences might not be immediately noticeable upon birth but may manifest later in life as permanent neurobehavioral problems. In order for drugs in maternal circulation to enter the fetal brain, they must overcome the placental barrier followed by a series of brain barriers, each consisting of cellular components and physiological mechanisms such as efflux transporters. The extent of protection they offer during development will provide valuable insights into the potential entry and the effects of CFTR modulators in the developing brain. This review aims to explore the current understanding of the safety of CFTR modulators, especially ivacaftor, during pregnancy and breastfeeding, characterize the pharmacokinetics and pharmacodynamics of ivacaftor, both under normal conditions and during pregnancy, to provide context for its potential impact on the developing brain. Finally, we discuss the determinants that need to be taken into consideration when investigating the entry of drugs into the fetus and newborn.GPR35 is a class A, rhodopsin-like G protein-coupled receptor (GPCR) first identified more than 20 years ago. In the intervening period, identification of strong expression in the lower intestine and colon, in a variety of immune cells including monocytes and a variety of dendritic cells, and in dorsal root ganglia has suggested potential therapeutic opportunities in targeting this receptor in a range of conditions. GPR35 is, however, unusual in a variety of ways that challenge routes to translation. These include the following (i) Although a substantial range and diversity of endogenous ligands have been suggested as agonist partners for this receptor, it officially remains defined as an "orphan" GPCR. (ii) Humans express two distinct protein isoform sequences, while rodents express only a single form. (iii) The pharmacologies of the human and rodent orthologues of GPR35 are very distinct, with variation between rat and mouse GPR35 being as marked as that between either of these species and the human forms. Herein we provide perspectives on each of the topics above as well as suggesting ways to overcome the challenges currently hindering potential translation. These include a better understanding of the extent and molecular basis for species selective GPR35 pharmacology and the production of novel mouse models in which both "on-target" and "off-target" effects of presumptive GPR35 ligands can be better defined, as well as a clear understanding of the human isoform expression profile and its significance at both tissue and individual cell levels.The CXCL12 chemokine receptor CXCR4 belongs to the GPCR superfamily and is often overexpressed in cancer, being involved in tumor progression and metastasis. How CXCR4 signaling integrates with other relevant oncogenic transduction pathways and the role of GPCR regulatory mechanisms in such contexts are not well-understood. Recent data indicate concurrent upregulation in certain tumors of CXCR4, EGF receptor (EGFR), and G protein-coupled receptor kinase 2 (GRK2), a signaling node functionally linked to both receptor types. We have investigated in a model system the effect of the EGFR and GRK2 status on CXCL12/CXCR4-mediated activation of Gi, the earliest step downstream of receptor activation. We find that overexpressed and activated EGFR reduces CXCR4-mediated Gi1 activation and that GRK2 phosphorylation at tyrosine residues is required to exert its inhibitory actions on CXCR4-Gi stimulation, suggesting a shared path of modulation. Our data point to a role for GRK2 in the crosstalk of the CXCR4 and EGFR signal transduction pathways in pathological contexts characterized by concurrent overactivation of these proteins.Intracellular pH plays critical roles in cell and tissue functions during processes such as metabolism, proliferation, apoptosis, ion transportation, endocytosis, muscle contraction and so on. It is thus an important biomarker that can readily be used to monitor the physiological status of a cell. Thus, disrupted intracellular pH may serve as an early indicator of cell dysfunction and deterioration. Various methods have been developed to detect cellular pH, such as pH-sensitive labeling reagents with fluorescent or Raman signals. However, excessive cellular uptake of these reagents will not only disrupt cell viability but also compromise effective long-term monitoring. Here, we present a novel fiber-optic fluorescent nanoprobe with a high spatial resolution for label-free, subcellular pH sensing. The probe has a fast response time (~20 seconds) with minimum invasiveness and excellent pH resolution (0.02 pH units) within a biologically relevant pH environment ranging from 6.17 to 8.11. Its applicability was demonstrated on cultured A549 lung cancer cells, and its efficacy was further testified in two typical cytotoxic cases using carbonylcyanide 3-chlorophenyl hydrazine, titanium dioxide, and nanoparticles. The probe can readily detect the pH variations among cells under toxin/nanoparticles administration, enabling direct monitoring of the early onset of physiological or pathological events with high spatiotemporal resolution. This platform has excellent promise as a minimum invasive diagnostic tool for pH-related cellular mechanism studies, such as inflammation, cytotoxicity, drug resistance, carcinogenesis, stem cell differentiation and so on.We propose a Bayesian adaptive design for early phase drug combination cancer trials incorporating ordinal grade of toxicities. Parametric models are used to describe the relationship between the dose combinations and the probabilities of the ordinal toxicities under the proportional odds assumption. Trial design proceeds by treating cohorts of two patients simultaneously receiving different dose combinations. Specifically, at each stage of the trial, we seek the dose of one agent by minimizing the Bayes risk with respect to a loss function given the current dose of the other agent. We consider two types of loss functions corresponding to the Continual Reassessment Method (CRM) and Escalation with Overdose Control (EWOC). At the end of the trial, we estimate the MTD curve as a function of Bayes estimates of the model parameters. TGF-beta activation We evaluate design operating characteristics in terms of safety of the trial and percent of dose recommendation at dose combination neighborhoods around the true MTD by comparing this design to the one that uses a binary indicator of DLT.
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