The aim of the article is to provide an update on medication use in infants admitted to the neonatal intensive care unit (NICU) in the United States and examine how use has changed over time.
We ...performed a retrospective review (2005-2010) of a large prospectively collected administrative database.
Medications most commonly administered during the study period were ampicillin, gentamicin, caffeine citrate, vancomycin, beractant, furosemide, fentanyl, dopamine, midazolam, and calfactant (56-681 exposures per 1,000 infants). Those with the greatest relative increase in use included azithromycin, sildenafil, and milrinone. Medications with the greatest relative decrease in use included theophylline, metoclopramide, and doxapram.
Medication use in the NICU has changed substantially over time, and only 35% of the most commonly prescribed medications are Food and Drug Administration -approved in infants.
Sustained persistence of chimeric antigen receptor T (CAR-T) cells is a key characteristic associated with long-term remission in patients with hematologic malignancies. Attempts to uncover ...mechanisms that enhance persistence and thus functionality will have a substantial impact in broadening application of CAR-T cell therapy, especially for solid tumors. In this issue of the JCI, Guedan et al. describe a promising strategy to limit T cell exhaustion and improve persistence by changing a single amino acid in the costimulatory domain of CD28. The authors demonstrated that this single amino acid substitution in CD28-based mesothelin CAR-T cells results in improved persistence and functionality in a xenograft model of pancreatic cancer. Furthermore, reciprocal alteration of the same residue in inducible costimulator-containing (ICOS-containing) CAR-T cells resulted in limited antitumor activity and persistence. These findings suggest that simple alterations in the costimulatory domain may enhance CAR-T cell persistence, warranting future evaluation in other CD28-costimulatory CARs in an effort to improve durable antitumor effects.
Chimeric antigen receptor (CAR) T-cell therapy has changed the landscape of immunotherapy for B-cell malignancies, including mature B-cell lymphomas. Although two CD19 CAR T-cell products have been ...commercially approved to treat relapsed/refractory B-cell lymphomas, outcomes in these patients remain inferior to those of patients with B-cell leukemia, regardless of therapy. Recent clinical studies and preclinical reports suggest that certain characteristics, such as the suppressive lymphoma tumor microenvironment and inferior endogenous T-cell fitness, may contribute to discrepant responses in these patients. In addition, these studies revealed that limited CAR T-cell persistence and tumor antigen escape, which also impact B-cell acute lymphoblastic leukemia, may play a more prominent role in lymphoma. Multiple promising strategies to overcome these barriers have advanced to clinical trials. In this review, we assess CAR T-cell therapies for pediatric relapsed/refractory mature B-cell lymphomas, potential obstacles diminishing antitumor activity and limiting CAR T-cell persistence, and current strategies to overcome these obstacles.
Transcriptional silencing of latent HIV-1 proviruses entails complex and overlapping mechanisms that pose a major barrier to in vivo elimination of HIV-1. We developed a new latency CRISPR screening ...strategy, called Latency HIV-CRISPR which uses the packaging of guideRNA-encoding lentiviral vector genomes into the supernatant of budding virions as a direct readout of factors involved in the maintenance of HIV-1 latency. We developed a custom guideRNA library targeting epigenetic regulatory genes and paired the screen with and without a latency reversal agent-AZD5582, an activator of the non-canonical NFκB pathway-to examine a combination of mechanisms controlling HIV-1 latency. A component of the Nucleosome Acetyltransferase of H4 histone acetylation (NuA4 HAT) complex, ING3, acts in concert with AZD5582 to activate proviruses in J-Lat cell lines and in a primary CD4+ T cell model of HIV-1 latency. We found that the knockout of ING3 reduces acetylation of the H4 histone tail and BRD4 occupancy on the HIV-1 LTR. However, the combination of ING3 knockout accompanied with the activation of the non-canonical NFκB pathway via AZD5582 resulted in a dramatic increase in initiation and elongation of RNA Polymerase II on the HIV-1 provirus in a manner that is nearly unique among all cellular promoters.
Antagonistic interactions drive host-virus evolutionary arms races, which often manifest as recurrent amino acid changes (i.e., positive selection) at their protein-protein interaction interfaces. ...Here, we investigated whether combinatorial mutagenesis of positions under positive selection in a host antiviral protein could enhance its restrictive properties. We tested approximately 700 variants of human MxA, generated by combinatorial mutagenesis, for their ability to restrict Thogotovirus (THOV). We identified MxA super-restrictors with increased binding to the THOV nucleoprotein (NP) target protein and 10-fold higher anti-THOV restriction relative to wild-type human MxA, the most potent naturally occurring anti-THOV restrictor identified. Our findings reveal a means to elicit super-restrictor antiviral proteins by leveraging signatures of positive selection. Although some MxA super-restrictors of THOV were impaired in their restriction of H5N1 influenza A virus (IAV), other super-restrictor variants increased THOV restriction without impairment of IAV restriction. Thus, broadly acting antiviral proteins such as MxA mitigate breadth-versus-specificity trade-offs that could otherwise constrain their adaptive landscape.
Chimeric antigen receptor (CAR) T cell (CAR-T) therapy has emerged as a revolutionary cancer treatment modality, particularly in children and young adults with B cell malignancies. Through clinical ...trials and real-world experience, much has been learned about the unique toxicity profile of CAR-T therapy. The past decade brought advances in identifying risk factors for severe inflammatory toxicities, investigating preventive measures to mitigate these toxicities, and exploring novel strategies to manage refractory and newly described toxicities, infectious risks, and delayed effects, such as cytopenias. Although much progress has been made, areas needing further improvements remain. Limited guidance exists regarding initial administration of tocilizumab with or without steroids and the management of inflammatory toxicities refractory to these treatments. There has not been widespread adoption of preventive strategies to mitigate inflammation in patients at high risk of severe toxicities, particularly children. Additionally, the majority of research related to CAR-T toxicity prevention and management has focused on adult populations, with only a few pediatric-specific studies published to date. Given that children and young adults undergoing CAR-T therapy represent a unique population with different underlying disease processes, physiology, and tolerance of toxicities than adults, it is important that studies be conducted to evaluate acute, delayed, and long-term toxicities following CAR-T therapy in this younger age group. In this pediatric-focused review, we summarize key findings on CAR-T therapy-related toxicities over the past decade, highlight emergent CAR-T toxicities, and identify areas of greatest need for ongoing research.
Background & Aims:
The cystic fibrosis transmembrane conductance regulator (CFTR) provides an important apical route for Cl
− secretion across intestinal epithelia. A thiazolidinone-type CFTR blocker ...(CFTR
inh-172) reduced cholera toxin-induced fluid accumulation in mouse intestinal loops. Here, we characterize the efficacy and pharmacodynamics of CFTR
inh-172 in blocking cAMP and cGMP induced Cl
−/fluid secretion in rodent and human intestine.
Methods & Results:
CFTR
inh-172 inhibited cAMP and cGMP agonist induced short-circuit current by >95% in T84 colonic epithelial cells (K
I ∼ 3 μmol/L) and in mouse and human intestinal sheets (K
I ∼ 9 μmol/L). A single intraperitoneal injection of CFTR
inh-172 (200 μg) blocked intestinal fluid secretion in a rat closed-loop model by >90% for cholera toxin and >70% for STa
Escherichia coli toxin. In mice, CFTR
inh-172 (20 μg) inhibited cholera toxin-induced intestinal fluid secretion by 90% (persistence t
1/2 ∼10 hours, K
I ∼ 5 μg) and STa toxin by 75% (K
I ∼ 10 μg). Tissue distribution and pharmacokinetic studies indicated intestinal CFTR
inh-172 accumulation facilitated by enterohepatic circulation. An oral CFTR
inh-172 preparation reduced fluid secretion by >90% in a mouse open-loop cholera model.
Conclusions:
A small molecule CFTR blocker markedly reduced intestinal ion and fluid secretion caused by cAMP/cGMP-dependent bacterial enterotoxins. CFTR inhibition may thus reduce fluid secretion in infectious secretory diarrheas.
PDF
