ABSTRACT
Immune checkpoint inhibitors (ICIs) have rejuvenated therapeutic approaches in oncology. Although responses tend to be durable, response rates vary in many cancer types. Thus, the identification and validation of predictive biomarkers is a key clinical priority, the answer to which is likely to lie in the tumour microenvironment (TME). A wealth of data demonstrates the huge impact of the TME on ICI response and resistance. However, these data also reveal the complexity of the TME composition including the spatiotemporal interactions between different cell types and their dynamic changes in response to ICIs. Here, we briefly review some of the modalities that sculpt the TME, in particular the metabolic milieu, hypoxia and the role of cancer-associated fibroblasts. We then discuss recent approaches to dissect the TME with a focus on single-cell RNA sequencing, spatial transcriptomics and spatial proteomics. We also discuss some of the clinically relevant findings these multi-modal analyses have yielded.
ABSTRACT
Aim To determine whether the introduction of a clinical pathway for the treatment of pyelonephritis in obstetric patients would improve outcomes. Methods This was a retrospective study conducted in a maternity hospital using quantitative analysis methods. Patients who met laboratory and clinical criteria for pyelonephritis during data collection were included. Results The study included analysis of 23 patients pre-intervention and 19 post-intervention. Baseline and patient characteristics were similar for both groups. A statistically significant difference was seen in 3 of 7 outcome measures. Increased use of gentamicin (13% Vs 52% p=0.006), Increased number of renal ultrasounds (17% Vs 47%, p=0.04) and increased use of prophylaxis (21% Vs 68%, p=0.003). The proportion of patients receiving ≥ 10 days of IV antimicrobials decreased from 48% to 21% post-intervention (p=0.07). Discussion This study has shown that the introduction of a pathway for the treatment of pyelonephritis in pregnancy had a positive impact on several important clinical outcomes.
Subject(s)
Critical Pathways , Obstetrics/standards , Pregnancy Complications/therapy , Pyelonephritis/therapy , Female , Humans , Pregnancy , Quality Improvement , Retrospective Studies , Young AdultABSTRACT
Whole-genome duplication (polyploidy) occurs frequently and repeatedly within species, often forming new lineages that contribute to biodiversity, particularly in plants. Establishment and persistence of new polyploids may be thwarted by competition with surrounding diploids; however, climatic niche shifts, where polyploids occupy different niches than diploid progenitors, may help polyploids overcome this challenge. We tested for climatic niche shifts between cytotypes using a new ordination approach and an unprecedentedly large data set containing young, conspecific diploids and polyploids. Despite expectations of frequent niche shifts, we show evidence for alternative patterns, such as niche conservatism and contraction, rather than a prevalent pattern of niche shifts. In addition, we explore how interpreting climatic niches plotted on environmental niche (principal component) axes can generate hypotheses about processes underlying niche dynamics. Dispersal capabilities or other life-history traits, rather than shifts to new climatic niches, could better explain polyploid persistence in the long term.
Subject(s)
Climate , Diploidy , Ecosystem , Polyploidy , Biodiversity , Plant Physiological Phenomena , Plants/geneticsABSTRACT
A program to improve upon the in vitro, in vivo, and physicochemical properties of N-hydroxyformamide TACE inhibitor GW 3333 (1) is described. Using the primary structure of pro-TNF-alpha, along with a homology model of the catalytic domain of TACE based on the X-ray diffraction coordinates of adamalysin, we synthesized N-hydroxyformamide TACE inhibitors containing a P2' arginine side chain. Introduction of nitro and sulfonyl electron-withdrawing groups covalently bound to the P2' guanidine moiety rendered the inhibitors electronically neutral at cellular pH and led to potent inhibition of TNF-alpha release from stimulated macrophages. Inhibitors containing these arginine mimetics were found to have increased solubility in simulated gastric fluid (SGF) relative to 1, allowing for the incorporation of lipophilic P1' side chains which had the effect of retaining potent TACE inhibition, but reducing potency against matrix metalloproteases (MMPs) thus increasing overall selectivity against MMP1, MMP3, and MMP9. Selected compounds showed good to excellent in vivo TNF inhibition when administered via subcutaneous injection. One inhibitor, 28a, with roughly 10x selectivity over MMP1 and MMP3 and high solubility in SGF, was evaluated in the rat zymosan-induced pleuisy model of inflammation and found to inhibit zymosan-stimulated pleural TNF-alpha elevation by 30%.
Subject(s)
Arginine/chemistry , Formamides/chemical synthesis , Guanidines/chemical synthesis , Metalloendopeptidases/antagonists & inhibitors , Protease Inhibitors/chemical synthesis , Thiazoles/chemical synthesis , Tumor Necrosis Factor-alpha/metabolism , ADAM Proteins , ADAM17 Protein , Animals , Catalytic Domain , Cell Line , Exudates and Transudates/metabolism , Female , Formamides/chemistry , Formamides/pharmacology , Guanidines/chemistry , Guanidines/pharmacology , Humans , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Lipopolysaccharides/pharmacology , Macrophage Activation , Male , Mice , Models, Molecular , Molecular Mimicry , Pleurisy/metabolism , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Rats , Rats, Inbred Lew , Solubility , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/pharmacologyABSTRACT
N-Hydroxyformamide-class metalloprotease inhibitors were designed and synthesized, which have potent broad-spectrum activity versus matrix metalloproteases and TNF-alpha converting enzyme (TACE). Compound 13c possesses good oral and intravenous pharmacokinetics in the rat and dog.
