Palladium(II) coordination with polyazacycloalkanes

International audienceIn view of the growing interest of palladium(II) for medical applications and the important role of polyamines in exploiting its properties, this review combines the published literature on the coordination of Pd(II) with small polyazacycloalkanes (three and four nitrogen atoms), such as 1,4,7-triazacyclononane, 1,5,9-triazacyclododecane, cyclen, cyclam, as well as their derivatives or close scaffolds such as pyclen. Finally, the rare examples of the use of aza-ligands with 103Pd and 109Pd radioisotopes for therapeutic purposes are also presented. The coordination of the Pd(II) ion is mainly square planar, often slightly distorted depending on the nature of the ligand. A few rare five-coordinated complexes with square pyramidal or trigonal bipyramidal geometries have been described in cases where the steric or topological requirements of the ligand outweigh the loss of stabilization due to geometric distortion. Considering the marked structural preference of Pd(II) for square planar coordination, this review allows us to propose hypotheses on the nature of new Pd(II) complexes whose properties could be exploited, especially in nuclear medicine

Characterization of the Peri-Membrane Fluorescence Phenomenon Allowing the Detection of Urothelial Tumor Cells in Urine

International audienceSimple Summary To detect bladder cancer (BC), urinary cytology and cystoscopy are the primary diagnostic tests used. Urine cytology is non-invasive, easy to collect, with medium sensitivity and high specificity. It is an effective way to detect high-grade BC, but it is less effective on low-grade BC because the rate of equivocal results is much higher, making them difficult to detect. Despite the implementation of new diagnostics, urinary cytology and cystoscopy remain the gold standard. Instead of looking for new diagnostics, one of the new research areas is the improvement of urinary cytology. Recently, the fluorescent properties of plasma membranes of urothelial tumor cells, called peri-membrane fluorescence, found in urinary cytology have been shown to be useful in improving the early detection of BC. The main objective of this study was to characterize the peri-membrane fluorescence allowing the detection of urothelial tumor cells in urine. Urine cytology is non-invasive, easy to collect, with medium sensitivity and a high specificity. It is an effective way to detect high-grade bladder cancer (BC), but it is less effective on low-grade BC because the rate of equivocal results is much higher. Recently, the fluorescent properties of plasma membranes of urothelial tumor cells (UTC) found in urine cytology have been shown to be useful in improving the early detection of BC. This phenomenon is called peri-membrane fluorescence (PMF). Based on previous studies that have identified the PMF on UTCs, the main objective was to characterize this phenomenon. For this study, a software was specially created to quantify the PMF of all tested cells and different treatments performed. PMF was not found to be a morphological and discriminating feature of UTCs, all cells in shape and not from urine show PMF. We were able to highlight the crucial role of plasma membrane integrity in the maintenance of PMF. Finally, it was found that the induction of a strong cellular stress induced a decrease in PMF, mimicking what was observed in non-tumor cells collected from urine. These results suggest that PMF is found in cells able to resist this stress, such as tumor cells

Relevance of Palladium to Radiopharmaceutical Development Considering Enhanced Coordination Properties of TE1PA

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Ventricular muscarinic receptor remodeling in patients with and without primary ventricular fibrillation. An imaging study

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Coupling between sediment biogeochemistry and phytoplankton development in a temperate freshwater marsh (Charente-Maritime, France): Evidence of temporal pattern

International audienceIn freshwater systems, sediment can be an important source for the internal loading of phosphate (PO4). The limiting character of this element in such system leads to consider this phenomenon in terms of eutrophication risks and water quality stakes. A four-months follow-up (January, March, April and May 2019) was carried out in a strong PO4 limited secondary channel from an artificial irrigation system of Charente Maritime (France) to link the mobilization of remineralization products in the upper 6 cm layer of sediment (conventional core slicing/centrifugation and DET probes) and the phytoplankton biomass dynamics in the water column. Results showed congruent patterns between the temporal succession of the organic matter mineralization processes in the sediment and the primary biomass dynamics in the water column. In January and March (considered in winter), PO4 proved to be retained by adsorption onto iron oxides in anoxic sediment since pore water nitrate inhibited for about a month the respiration of metal oxides in the first cm of sediment, thus limiting PO4 availability and the phytoplankton growth. In April and May (early spring), after exhaustion of pore water nitrate, the dissolutive reduction of iron oxides released PO4 into pore water generated a significant diffusive outgoing flux from the sediment to the water column with a maximum in April (-1.10E-04±2.81E-05 nmol cm-2 s-1). This release coincided with the nanophytoplankton bloom (5.50 µg Chla L-1) and a potential increase of PO4 concentration in the water column. This work provides some insight on the importance of benthic-pelagic coupling in anthropogenic systems. This conceptual model has to be deployed on other sites of interest where internal loading of P takes precedence over external inputs and nitrate mitigation drives its benthic recycling and ultimately its bioavailability. This is to be essential to characterize the aquatic environment quality in order to limit eutrophication risks

Drivers for primary producers’ dynamics: New insights on annual benthos pelagos monitoring in anthropised freshwater marshes (Charente-Maritime, France)

International audienceWetlands, especially marshes, support many services such as carbon catchment control or water purification led by primary producers such as phytoplankton and microphytobenthos (PB). The impact of the sedimentary compartment, as source and sink of essential nutrients for the water column, is often neglected in the study of their dynamics and water purification capacity of the systems. This work compared monthly (between February 2020 and April 2021) the benthic and pelagic primary producers’ dynamics in two anthropised freshwater marshes (Marans and Genouillé), with the simultaneous follow-up of physico-chemical parameters of the water column and nutrient fluxes at the sediment-water (SWI) interface. It was suggested a strong contribution of phytoplankton (pumping) and the benthic compartment (denitrification) to the water purification of these two nitrates (NO3-)-rich marshes. Total phytoplankton production fluctuated between ~5 (winter) and 1500 mg C m-3 d-1 (fall) at Marans and between 40 (winter) and ~750 mg C m-3 d-1 (spring) at Genouillé. At Marans, soluble reactive phosphorus (SRP) benthic effluxes (-2.101 to -6.102 µmol m-2 d-1 in fall and summer respectively) coincided with phytoplankton bloom periods. These effluxes were inhibited by NO3- penetration in the sediment (0 to 5.104 µmol m-2 d-1), by inhibiting iron respiration. At Genouillé, inhibition of SRP effluxes depended on denitrification rate and on P stocks in the sediment, where slight SRP effluxes (-101 µmol m-2 d-1) could have co-occurred with slight NO3- influxes (5.102 µmol m-2 d-1) in spring. The presence of PB (between 10-60 and 40-120 mg gsed-1 at Marans and Genouillé respectively), suggested a strong contribution of the benthic compartment to the total primary production (benthic and pelagic through resuspension processes) in these environments. This work encourages to consider the benthos and the pelagos as a unicum to provide better sustainable management of such systems and limit eutrophication risks in coastal areas

TGFβ-induced long non-coding RNA LINC00313 activates Wnt signaling and promotes cholangiocarcinoma

International audienceCholangiocarcinoma is a devastating liver cancer characterized by high aggressiveness and therapy resistance, resulting in poor prognosis. Long non-coding RNAs and signals imposed by oncogenic pathways, such as transforming growth factor beta (TGF beta), frequently contribute to cholangiocarcinogenesis. Here, we explore novel effectors of TGF beta signalling in cholangiocarcinoma. LINC00313 is identified as a novel TGF beta target gene. Gene expression and genome-wide chromatin accessibility profiling reveal that nuclear LINC00313 transcriptionally regulates genes involved in Wnt signalling, such as the transcriptional activator TCF7. LINC00313 gain-of-function enhances TCF/LEF-dependent transcription, promotes colony formation in vitro and accelerates tumour growth in vivo. Genes affected by LINC00313 over-expression in CCA tumours are associated with KRAS and TP53 mutations and reduce overall patient survival. Mechanistically, ACTL6A and BRG1, subunits of the SWI/SNF chromatin remodelling complex, interact with LINC00313 and affect TCF7 and SULF2 transcription. We propose a model whereby TGF beta induces LINC00313 in order to regulate the expression of hallmark Wnt pathway genes, in co-operation with SWI/SNF. By modulating key genes of the Wnt pathway, LINC00313 fine-tunes Wnt/TCF/LEF-dependent transcriptional responses and promotes cholangiocarcinogenesis

TGFβ-induced FOXS1 controls epithelial-mesenchymal transition and predicts a poor prognosis in liver cancer

International audienceTransforming growth factor beta (TGFβ) plays a key role in tumor progression, notably as a potent inducer of epithelial-mesenchymal transition (EMT). However, all of the molecular effectors driving TGFβ-induced EMT are not fully characterized. Here, we report that forkhead box S1 (FOXS1) is a SMAD (mothers against decapentaplegic)dependent TGFβ-induced transcription factor, which regulates the expression of genes required for the initial steps of EMT (e.g., snail family transcription repressor 1) and to maintain a mesenchymal phenotype in hepatocellular carcinoma (HCC) cells. In human HCC, we report that FOXS1 is a biomarker of poorly differentiated and aggressive tumor subtypes. Importantly, FOXS1 expression level and activity are associated with a poor prognosis (e.g., reduced patient survival), not only in HCC but also in colon, stomach, and kidney cancers. Conclusion: FOXS1 constitutes a clinically relevant biomarker for tumors in which the pro-metastatic arm of TGFβ is active (i.e., patients who may benefit from targeted therapies using inhibitors of the TGFβ pathway). (Hepatology Communications 2021;0:1-15)

Orthotopic model of lung cancer: isolation of bone micro-metastases after tumor escape from Osimertinib treatment

International audienceBackground: Osimertinib is a third generation tyrosine kinase inhibitor (TKI) that targets the epidermal growth factor receptor (EGFR) in lung cancer. However, although this molecule is not subject to some of the resistance mechanisms observed in response to first generation TKIs, ultimately, patients relapse because of unknown resistance mechanisms. New relevant non-small cell lung cancer (NSCLC) mice models are therefore required to allow the analysis of these resistance mechanisms and to evaluate the efficacy of new therapeutic strategies. Methods: Briefly, PC-9 cells, previously modified for luciferase expression, were injected into the tail vein of mice. Tumor implantation and longitudinal growth, almost exclusively localized in the lung, were evaluated by bioluminescence. Once established, the tumor was treated with osimertinib until tumor escape and development of bone metastases. Results: Micro-metastases were detected by bioluminescence and collected for further analysis. Conclusion: We describe an orthotopic model of NSCLC protocol that led to lung primary tumor nesting and, after osimertinib treatment, by metastases dissemination, and that allow the isolation of these small osimertinib-resistant micro-metastases. This model provides new biological tools to study tumor progression from the establishment of a lung tumor to the generation of drug-resistant micro-metastases, mimicking the natural course of the disease in human NSCLC patients

Blood co-expression modules identify potential modifier genes of diabetes and lung function in cystic fibrosis

International audienceCystic fibrosis (CF) is a rare genetic disease that affects the respiratory and digestive systems. Lung disease is variable among CF patients and associated with the development of comorbidities and chronic infections. The rate of lung function deterioration depends not only on the type of mutations in CFTR, the disease-causing gene, but also on modifier genes. In the present study, we aimed to identify genes and pathways that (i) contribute to the pathogenesis of cystic fibrosis and (ii) modulate the associated comorbidities. We profiled blood samples in CF patients and healthy controls and analyzed RNA-seq data with Weighted Gene Correlation Network Analysis (WGCNA). Interestingly, lung function, body mass index, the presence of diabetes, and chronic P. aeruginosa infections correlated with four modules of co-expressed genes. Detailed inspection of networks and hub genes pointed to cell adhesion, leukocyte trafficking and production of reactive oxygen species as central mechanisms in lung function decline and cystic fibrosis-related diabetes. Of note, we showed that blood is an informative surrogate tissue to study the contribution of inflammation to lung disease and diabetes in CF patients. Finally, we provided evidence that WGCNA is useful to analyze-omic datasets in rare genetic diseases as patient cohorts are inevitably small