Purpose
Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor outcome and limited therapeutic options. Imaging of IPF is limited to high-resolution computed tomography (HRCT) which ...is often not sufficient for a definite diagnosis and has a limited impact on therapeutic decision and patient management. Hypoxia of the lung is a significant feature of IPF but its role on disease progression remains elusive. Thus, the aim of our study was to evaluate hypoxia imaging with
18
FFMISO as a predictive biomarker of disease progression and therapy efficacy in preclinical models of lung fibrosis in comparison with
18
FFDG.
Methods
Eight-week-old C57/BL6 mice received an intratracheal administration of bleomycin (BLM) at day (D) 0 to initiate lung fibrosis. Mice received pirfenidone (300 mg/kg) or nintedanib (60 mg/kg) by daily gavage from D9 to D23. Mice underwent successive PET/CT imaging at several stages of the disease (baseline, D8/D9, D15/D16, D22/D23) with
18
FFDG and
18
FFMISO. Histological determination of the lung expression of HIF-1α and GLUT-1 was performed at D23.
Results
We demonstrate that mean lung density on CT as well as
18
FFDG and
18
FFMISO uptakes are upregulated in established lung fibrosis (1.4-, 2.6- and 3.2-fold increase respectively). At early stages, lung areas with
18
FFMISO uptake are still appearing normal on CT scans and correspond to areas which will deteriorate towards fibrotic lesions at later timepoints. Nintedanib and pirfenidone dramatically and rapidly decreased mean lung density on CT as well as
18
FFDG and
18
FFMISO lung uptakes (pirfenidone: 1.2-, 2.9- and 2.6-fold decrease; nintedanib: 1.2-, 2.3- and 2.5-fold decrease respectively). Early
18
FFMISO lung uptake was correlated with aggressive disease progression and better nintedanib efficacy.
Conclusion
18
FFMISO PET imaging is a promising tool to early detect and monitor lung fibrosis progression and therapy efficacy.
IL-1RAP, a Key Therapeutic Target in Cancer Frenay, Jame; Bellaye, Pierre-Simon; Oudot, Alexandra ...
International journal of molecular sciences,
11/2022, Letnik:
23, Številka:
23
Journal Article
Recenzirano
Odprti dostop
Cancer is a major cause of death worldwide and especially in high- and upper-middle-income countries. Despite recent progress in cancer therapies, such as chimeric antigen receptor T (CAR-T) cells or ...antibody-drug conjugate (ADC), new targets expressed by the tumor cells need to be identified in order to selectively drive these innovative therapies to tumors. In this context, IL-1RAP recently showed great potential to become one of these new targets for cancer therapy. IL-1RAP is highly involved in the inflammation process through the interleukins 1, 33, and 36 (IL-1, IL-33, IL-36) signaling pathways. Inflammation is now recognized as a hallmark of carcinogenesis, suggesting that IL-1RAP could play a role in cancer development and progression. Furthermore, IL-1RAP was found overexpressed on tumor cells from several hematological and solid cancers, thus confirming its potential involvement in carcinogenesis. This review will first describe the structure and genetics of IL-1RAP as well as its role in tumor development. Finally, a focus will be made on the therapies based on IL-1RAP targeting, which are now under preclinical or clinical development.
Cancer immunotherapy has tremendous promise, but it has yet to be clinically applied in a wider variety of tumor situations. Many therapeutic combinations are envisaged to improve their ...effectiveness. In this way, strategies capable of inducing immunogenic cell death (e.g., doxorubicin, radiotherapy, hyperthermia) and the reprogramming of the immunosuppressive tumor microenvironment (TME) (e.g., M2-to-M1-like macrophages repolarization of tumor-associated macrophages (TAMs)) are particularly appealing to enhance the efficacy of approved immunotherapies (e.g., immune checkpoint inhibitors, ICIs). Due to their modular construction and versatility, iron oxide-based nanomedicines such as superparamagnetic iron oxide nanoparticles (SPIONs) can combine these different approaches in a single agent. SPIONs have already shown their safety and biocompatibility and possess both drug-delivery (e.g., chemotherapy, ICIs) and magnetic capabilities (e.g., magnetic hyperthermia (MHT), magnetic resonance imaging). In this review, we will discuss the multiple applications of SPIONs in cancer immunotherapy, focusing on their theranostic properties to target TAMs and to generate MHT. The first section of this review will briefly describe immune targets for NPs. The following sections will deal with the overall properties of SPIONs (including MHT). The last section is dedicated to the SPION-induced immune response through its effects on TAMs and MHT.
Background
During anthracycline treatment of cancer, there is a lack for biomarkers of cardiotoxicity besides the cardiac dysfunction. The objective of the present study was to compare
18
FFDG and
...123
IMIBG (metaiodobenzylguanidine) in a longitudinal study in a doxorubicin-induced cardiotoxicity rat model.
Methods
Male Wistar Han rats were intravenously administered 3 times at 10 days’ interval with saline or doxorubicin (5 mg/kg).
123
IMIBG SPECT/CT (single photon emission computed tomography-computed tomography) and simultaneous
18
FFDG PET (positron emission tomography)/7 Tesla cardiac MR (magnetic resonance) imaging acquisitions were performed at 24 h interval before first doxorubicin / saline injection and every 2 weeks during 6 weeks. At 6 weeks, the heart tissue was collected for histomorphometry measurements.
Results
At week 4, left ventricle (LV) end-diastolic volume was significantly reduced in the doxorubicin group. At week 6, the decreased LV end-diastolic volume was maintained, and LV end-systolic volume was increased resulting in a significant reduction of LV ejection fraction (47 ± 6% vs. 70 ± 3%). At weeks 4 and 6, but not at week 2, myocardial
18
FFDG uptake was decreased compared with the control group (respectively, 4.2 ± 0.5%ID/g and 9.2 ± 0.8%ID/g at week 6). Moreover,
18
FFDG cardiac uptake correlated with cardiac function impairment. In contrast, from week 2, a significant decrease of myocardial
123
IMIBG heart to mediastinum ratio was detected in the doxorubicin group and was maintained at weeks 4 and 6 with a 45.6% decrease at week 6.
Conclusion
This longitudinal study precises that after doxorubicin treatment, cardiac
123
IMIBG uptake is significantly reduced as early as 2 weeks followed by the decrease of the LV end-diastolic volume and
18
FFDG uptake at 4 weeks and finally by the increase of LV end-systolic volume and decrease of LV ejection fraction at 6 weeks. Cardiac innervation imaging should thus be considered as an early key feature of anthracycline cardiac toxicity.
Superparamagnetic iron oxide nanoparticles were developed as positron emission tomography (PET) and magnetic resonance imaging (MRI) bimodal imaging agents. These nanoparticles (NPs), with a specific ...nanoflower morphology, were first synthesized and simultaneously functionalized with 3,4-dihydroxy-l-phenylalanine (LDOPA) under continuous hydrothermal conditions. The resulting NPs exhibited a low hydrodynamic size of 90 ± 2 nm. The functional groups of LDOPA (−NH2 and −COOH) were successfully used for the grafting of molecules of interest in a second step. The nanostructures were modified by poly(ethylene glycol) (PEG) and a new macrocyclic chelator MANOTA for further 64Cu radiolabeling for PET imaging. The functionalized NPs showed promising bimodal (PET and MRI) imaging capability with high r 2 and r 2* (T 2 and T 2* relaxivities) values and good stability. They were mainly uptaken from liver and kidneys. No cytotoxicity effect was observed. These NPs appear as a good candidate for bimodal tracers in PET/MRI.
Although introduced decades ago, few cyanoacrylate glues have been approved for endovascular use, despite evidence of their usefulness, notably for complex procedures suchas hemostatic embolization. ...Indications include massive bleeding requiring emergent hemostasis and prevention of severe bleeding during scheduled surgery to remove a hypervascular tumor. Adding radiopaque Lipiodol Ultra Fluid® (LUF) modulates glue polymerization and allows fluoroscopic guidance, but few comparative in vivo studies have assessed the impact of the resulting change in glue concentration or of other factors such as target-vessel blood flow. In a rabbit model, we used ex vivo X-ray microtomography to assess the results of in vivo renal-artery embolization by various mixtures of N-butyl cyanoacrylate (NBCA), metacryloxysulfolane, and LUF. Overall, penetration to the superficial interlobular arteries was achieved in about two-thirds of cases and into the capillaries in nearly half the cases, while cast fragmentation was seen in slightly more than half the cases. Greater NBCA dilution and the blocked-blood-flow technique were independently associated with greater distality of penetration. Blocked-blood-flow injection was independently associated with absence of fragmentation, capillary penetration, a shorter cast-to-capsule distance, and higher cast attenuation. A larger mixture volume was independently associated with higher indexed cast ratio and deeper penetration. Finally, microtomography is an adapted tool to assess ex vivo distribution of glue cast.
Aims Oxidative stress, i.e. imbalance between reactive oxygen species (ROS) and antioxidant defences, contributes to the progression of chronic heart failure (CHF). Acute inhibition of xanthine ...oxidase (XO), which produces ROS, improves mechanical efficiency of the failing heart, but whether long-term XO inhibition exerts beneficial effects in CHF is unknown. Methods and results In rats with established CHF induced by left coronary ligation, we assessed the effects of a 5-day and a 10-week treatment with the XO inhibitor allopurinol (50 mg kg−1 day−1) on haemodynamics and left ventricular (LV) function and structure. Both acute and chronic allopurinol treatment increase cardiac output without modification of arterial pressure, but only chronic allopurinol treatment reduces LV end-diastolic pressure and LV relaxation constant. Chronic allopurinol treatment decreases both LV systolic and diastolic diameters, but acute allopurinol treatment only decreases LV systolic diameter. Moreover, chronic allopurinol decreases LV weight and collagen density. Despite XO inhibition after acute and chronic allopurinol treatment, as both treatments reduce uric acid plasma levels, only acute allopurinol treatment reduces LV ROS determined using electron spin resonance spectroscopy. However, the CHF-enhanced myocardial thiobarbituric acid reactive substances levels were never modified. Conclusion In experimental CHF, long-term allopurinol treatment, initiated in a pathological state of overt CHF, improves LV haemodynamics and function and prevents LV remodelling. These long-term effects are, at least partially, caused by a transient reduction of myocardial ROS shortly after initiation of allopurinol treatment, but whether other mechanism(s), independent of myocardial redox ‘status’, such as reduced inflammation, are implicated remains to be confirmed.
Dual‐labeled biomolecules constitute a new generation of bioconjugates with promising applications in therapy and diagnosis. Unfortunately, the development of these new families of biologics is ...hampered by the technical difficulties associated with their construction. In particular, the site specificity of the conjugation is critical as the number and position of payloads can have a dramatic impact on the pharmacokinetics of the bioconjugate. Herein, we introduce dichlorotetrazine as a trivalent platform for the selective double modification of proteins on cysteine residues. This strategy is applied to the dual labeling of albumin with a macrocyclic chelator for nuclear imaging and a fluorescent probe for fluorescence imaging.
Two for one: A two‐step strategy enables the double modification of proteins on one cysteine residue. This approach takes advantage of the selective reaction of monosubstituted chlorotetrazines with thiols under mild conditions and their ability to undergo orthogonal inverse‐electron‐demand Diels–Alder reactions.
Summary
Aging triggers several abnormalities in muscle glycolytic fibers including increased proteolysis, reactive oxygen species (ROS) production and apoptosis. Since the mitochondria are the main ...site of substrate oxidation, ROS production and programmed cell death, we tried to know whether the cellular disorders encountered in sarcopenia are due to abnormal mitochondrial functioning. Gastrocnemius mitochondria were extracted from adult (6 months) and aged (21 months) male Wistar rats. Respiration parameters, opening of the permeability transition pore and ROS production, with either glutamate (amino acid metabolism) or pyruvate (glucose metabolism) as a respiration substrate, were evaluated at different matrix calcium concentrations. Pyruvate dehydrogenase and respiratory complex activities as well as their contents measured by Western blotting analysis were determined. Furthermore, the fatty acid profile of mitochondrial phospholipids was also measured. At physiological calcium concentration, state III respiration rate was lowered by aging in pyruvate conditions (−22%), but not with glutamate. The reduction of pyruvate oxidation resulted from a calcium‐dependent inactivation of the pyruvate dehydrogenase system and could provide for the well‐known proteolysis encountered during sarcopenia. Matrix calcium loading and aging increased ROS production. They also reduced the oxidative phosphorylation. This was associated with lower calcium retention capacities, suggesting that sarcopenic fibers are more prone to programmed cell death. Aging was also associated with a reduced mitochondrial superoxide dismutase activity, which does not intervene in toxic ROS overproduction but could explain the lower calcium retention capacities. Despite a lower content, cytochrome c oxidase displayed an increased activity associated with an increased n−6/n−3 polyunsaturated fatty acid ratio of mitochondrial phospholipids. In conclusion, we propose that mitochondria obtained from aged muscle fibers display several functional abnormalities explaining the increased proteolysis, ROS overproduction and vulnerability to apoptosis exhibited by sarcopenic muscle. These changes appear to be related to modifications of the fatty acid profile of mitochondrial lipids.
The therapeutic efficacy and adverse impacts of nanoparticles (NPs) are strongly dependent on their systemic circulation time. The corona proteins adsorbed on the NPs determine their plasma ...half-lives, and hence, it is crucial to identify the proteins shortening or extending their circulation time. In this work, the in vivo circulation time and corona composition of superparamagnetic iron oxide nanoparticles (SPIONs) with different surface charges/chemistries were analyzed over time. SPIONs with neutral and positive charges showed the longest and shortest circulation times, respectively. The most striking observation was that corona-coated NPs with similar opsonin/dysopsonin content showed different circulation times, implying these biomolecules are not the only contributing factors. Long-circulating NPs adsorb higher concentrations of osteopontin, lipoprotein lipase, coagulation factor VII, matrix Gla protein, secreted phosphoprotein 24, alpha-2-HS-glycoprotein, and apolipoprotein C-I, while short-circulating NPs adsorb higher amounts of hemoglobin. Therefore, these proteins may be considered to be determining factors governing the NP systemic circulation time.
![[18F]FMISO PET/CT imaging o...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/1619-7070_1619-7089/small "[18F]FMISO PET/CT imaging of hypoxia as a non-invasive biomarker of disease progression and therapy efficacy in a preclinical model of pulmonary fibrosis: comparison with the [18F]FDG PET/CT approach")
PDF
![[123I]MIBG is a better earl...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/2191-219X/small "[123I]MIBG is a better early marker of anthracycline cardiotoxicity than [18F]FDG: a preclinical SPECT/CT and simultaneous PET/MR study")
