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"Mathieu Romain"
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The intervening domain is required for DNA-binding and functional identity of plant MADS transcription factors
The MADS transcription factors (TF) are an ancient eukaryotic protein family. In plants, the family is divided into two main lineages. Here, we demonstrate that DNA binding in both lineages absolutely requires a short amino acid sequence C-terminal to the MADS domain (M domain) called the Intervening domain (I domain) that was previously defined only in type II lineage MADS. Structural elucidation of the MI domains from the floral regulator, SEPALLATA3 (SEP3), shows a conserved fold with the I domain acting to stabilise the M domain. Using the floral organ identity MADS TFs, SEP3, APETALA1 (AP1) and AGAMOUS (AG), domain swapping demonstrate that the I domain alters genome-wide DNA-binding specificity and dimerisation specificity. Introducing AG carrying the I domain of AP1 in the Arabidopsis
ap1
mutant resulted in strong complementation and restoration of first and second whorl organs. Taken together, these data demonstrate that the I domain acts as an integral part of the DNA-binding domain and significantly contributes to the functional identity of the MADS TF.
MADS transcription factors regulate multiple aspects of plant development. Here the authors show that the intervening I domain is conserved in both type I and type II plant MADS lineages and contributes to the functional identity of the protein by influencing both DNA binding activity and dimerisation specificity.
Journal Article
Nelson Mandela
\"Learn how activist, philanthropist, and South African president Nelson Mandela opposed apartheid and battled racism.\"--Page 4 of cover.
Book
Insecticide Resistance in the Dengue Vector Aedes aegypti from Martinique: Distribution, Mechanisms and Relations with Environmental Factors
Dengue is an important mosquito borne viral disease in Martinique Island (French West Indies). The viruses responsible for dengue are transmitted by Aedes aegypti, an indoor day-biting mosquito. The most effective proven method for disease prevention has been by vector control by various chemical or biological means. Unfortunately insecticide resistance has already been observed on the Island and recently showed to significantly reduce the efficacy of vector control interventions. In this study, we investigated the distribution of resistance and the underlying mechanisms in nine Ae. aegypti populations. Statistical multifactorial approach was used to investigate the correlations between insecticide resistance levels, associated mechanisms and environmental factors characterizing the mosquito populations. Bioassays revealed high levels of resistance to temephos and deltamethrin and susceptibility to Bti in the 9 populations tested. Biochemical assays showed elevated detoxification enzyme activities of monooxygenases, carboxylesterases and glutathione S-tranferases in most of the populations. Molecular screening for common insecticide target-site mutations, revealed the presence of the \"knock-down resistance\" V1016I Kdr mutation at high frequency (>87%). Real time quantitative RT-PCR showed the potential involvement of several candidate detoxification genes in insecticide resistance. Principal Component Analysis (PCA) performed with variables characterizing Ae. aegypti from Martinique permitted to underline potential links existing between resistance distribution and other variables such as agriculture practices, vector control interventions and urbanization. Insecticide resistance is widespread but not homogeneously distributed across Martinique. The influence of environmental and operational factors on the evolution of the resistance and mechanisms are discussed.
Journal Article
Targeting the PD-1/PD-L1 Pathway in Renal Cell Carcinoma
Renal cell carcinoma encompass distinct diseases with different pathologic features and distinct molecular pathways. Immune checkpoint inhibitors targeting the programmed death receptor ligand 1 (PD-L1)/programmed death receptor 1 (PD-1) pathway alone or in combination have greatly changed clinical management of metastatic renal cell carcinoma, now competing with antiangiogenic drugs in monotherapy for first-line treatment. However, long-term response rates are low, and biomarkers are needed to predict treatment response. Quantification of PD-L1 expression by immunohistochemistry was developed as a promising biomarker in clinical trials, but with many limitations (different antibodies, tumour heterogeneity, specimens, and different thresholds of positivity). Other biomarkers, including tumour mutational burden and molecular signatures, are also developed and discussed in this review.
Journal Article
Comparison of 1800 Robotic and Open Partial Nephrectomies for Renal Tumors
Background
Only a few studies have compared the outcomes of robotic partial nephrectomy (RPN) and open partial nephrectomy (OPN). This study aimed to compare perioperative and oncologic outcomes of RPN and OPN.
Methods
The data of all patients who underwent partial nephrectomy from 2006 to 2014 in six academic departments of urology were retrospectively collected. Perioperative outcomes were compared between OPN and RPN patients. Cancer-specific survival (CSS) and recurrence-free survival (RFS) were estimated using the Kaplan–Meier method and compared using the log-rank test.
Results
The study included 1800 patients: 937 who underwent RPN and 863 who underwent OPN. The patients in the robotic group had smaller tumors (33.1 vs. 39.9 mm;
p
< 0.001) but comparable RENAL scores (6.8 vs. 6.7;
p
= 0.37). The complication rate was higher in the OPN group (28.6 vs. 18 %;
p
< 0.001). The OPN patients had greater estimated blood loss (359.5 vs. 275 ml;
p
< 0.001) and more frequent hemorrhagic complications (12.1 vs. 6.9 %;
p
< 0.001). The robotic approach was associated with a shorter warm ischemia time (WIT 15.7 vs. 18.6 min;
p
< 0.001) and a shorter hospital of stay (4.7 vs. 10.1 days;
p
< 0.001). In the propensity score-weighted analysis, the inverse probability of treatment weighting adjusted odds ratio for the risk of complication after OPN versus RPN was 2.11 (95 % confidence interval, 1.53–2.91;
p
< 0.001). After a median postoperative follow-up period of 13 months for OPN and 39 months for RPN (
p
< 0.001), CSS and RFS were similar in the two groups. In the multivariate analysis, RPN showed an impact on the occurrence of a complication but had no effect on WIT or RFS.
Conclusion
In this study, RPN was less morbid than OPN, with lower complications, less blood loss, and a shorter hospital of stay. The intermediate-term oncologic outcomes were similar in the two groups.
Journal Article
Adherent perinephric fat affects perioperative outcomes after partial nephrectomy: a systematic review and meta-analysis
To investigate the association of adherent perinephric fat (APF) with perioperative outcomes, we conducted a systematic review and meta-analysis of the literature to clarify the impact of APF in patients undergoing partial nephrectomy. A systematic literature search using the Medline, Scopus, and Cochrane databases was performed in April 2019 and updated in November 2019 to identify studies investigating the effect of APF on perioperative outcomes in patients treated with partial nephrectomy with the aim of evaluating its impact on intraoperative, postoperative and oncological outcomes. The Newcastle–Ottawa Scale (NOS) was used to assess the quality of the included studies. A total of 1534 patients in nine nonrandomized, observational studies met our inclusion criteria. Patients with APF were significantly older (p = 0.0001), had a higher BMI (p = 0.0001) and were predominately male (p = 0.003). APF was associated with a higher operative time (p = 0.001) and higher blood loss (p = 0.002). No significant impact of APF was found in terms of postoperative complications, positive margins or length of stay. APF was also found to be associated with malignant renal histology of RCC on final pathology (p = 0.005). APF was associated with some adverse perioperative outcomes, especially a prolonged operating time and higher blood loss. In addition, APF was also associated with underlying renal malignancy, but the precise causal mechanism requires further exploration.
Journal Article
PARP inhibitors in prostate cancers, is it time for combinations?
Despite several improvements in outcomes, metastatic prostate cancer remains deadly. Alterations in the homologous recombination repair (HRR) pathway are associated with more aggressive disease. Olaparib and rucaparib, two poly-ADP-ribose polymerase (PARP) inhibitors, have received approval from the authorities of several countries for their anti-tumoral effects in patients with metastatic castration-resistant prostate cancers harboring HRR gene alterations, in particular BRCA2. More recently, it has been hypothesized that new hormonal therapies (NHTs) and PARP inhibitors (PARPi) could have synergistic actions and act independently of HRR deficiency. This review proposes to discuss the advantages and disadvantages of PARPi used as monotherapy or in combination with NHTs and whether there is a need for molecular selection.
Journal Article
Prevention and management of PARP inhibitor-related haematological toxicities in prostate cancer: French expert opinion using the Delphi method
Background:
Haematological toxicities (anaemia, neutropenia and thrombocytopenia), a known class effect of poly-ADP ribose polymerase inhibitors (PARPi) may limit exposure to PARPi and therefore impact efficacy.
Objective:
This study aimed to provide practical and detailed recommendations for the prevention and management of these toxicities in metastatic prostate cancer in the real world.
Design:
A national consensus study was performed using a modified Delphi methodology.
Methods:
A multidisciplinary steering committee of 9 French experts formulated and submitted 38 statements to the vote of 33 French healthcare professionals experienced in oncology and PARPi in prostate and/or breast/ovarian cancers.
Results:
All recommendations achieved a consensus. Before initiating PARPi, haematological disorders should be investigated and appropriate corrective measures implemented. The haemoglobin level should ideally be ⩾10 g/dl and a minimum delay of 4 weeks should be respected after chemotherapy. Monitoring should be frequent for the first 3 months of treatment, at least every 15 days, and even more frequent in patients at high-risk of toxicity. In the event of symptomatic grade 2 or 3 anaemia, grade 2 or 3 thrombocytopenia and grade 3 neutropenia, PARPi treatment should be discontinued until return to grade 1. Transfusion may be considered in symptomatic grade 2 or 3 anaemia. Myelodysplastic syndrome/acute myeloid leukaemia should be suspected in cases of cytopenia persisting beyond 4 weeks or changes in the blood count after maintenance of an optimal therapeutic dose over the long term.
Conclusion:
These proposals complement existing recommendations to guide healthcare professionals in real-world practice, and so optimise metastatic prostate cancer patient’s ability to maximally benefit from PARPi.
Journal Article