Regulation of the floral transition and inflorescence development by the bZIP transcription factor FD in Arabidopsis thaliana

The integration of signals in response to endogenous and exogenous stimuli at the shoot apical meristem (SAM) determines the timing of the transition from vegetative to reproductive development in Arabidopsis. Under inductive long-day (LD) photoperiods, FLOWERING LOCUS T (FT) and the bZIP transcription factor FD form the large transcriptional complex FD–(14-3-3)–FT/TSF at the SAM. Within this complex, FD is the DNA-binding component and some target genes of FD have been well characterized. The fd mutant is late flowering under LD conditions due to the improper regulation of its targets. Despite increased knowledge on the regulatory pathways that act through the FD–(14-3-3)–FT/TSF complex, the cis-regulatory elements that are required for the binding of FD to its targets remain poorly defined, and it is unclear how different targets show distinct spatiotemporal expression patterns. For example, although FD enhances FRUITFULL (FUL) transcription within the SAM, APETALA1 (AP1) transcription is promoted by FD later in development and AP1 transcripts are specific to floral primordia. Furthermore, the subset of direct targets that are involved in the floral transition before the upregulation of FUL and AP1 remain uncharacterized. During this PhD, I generated a transgenic fd mutant line in which the translocation of FD into the nucleus can be induced at different developmental time points. Induction of FD in this line promoted flowering, and showed that FD activity was required for several days to complete floral transition. I performed RNA-seq on apices of these plants following FD induction and identified putative additional components of the FD transcriptional network. The earliest targets of FD from this whole-transcriptome analysis could not be linked to floral transition, although FUL and AP1 were upregulated at later stages, confirming that floral transition occurred following FD induction. Much evidence exists to support that FUL is regulated by FD and I identified two putative conserved binding sites in the proximal promoter of FUL. However, mutation of these cis-elements did not affect flowering time nor the accumulation or pattern of FUL protein at the SAM. Under non-inductive short-day (SD) conditions, the SQUAMOSA PROMOTER BINDING PROTEIN-LIKE 15 (SPL15) protein also binds to FUL and regulates its expression. Although FD and SPL15 regulate FUL through the LD and SD pathways, respectively, I hypothesise that they do not compete at the promoter level and that activation of FUL by FD can occur indirectly through FD-mediated activation of other transcription factors or that FD binds to redundant sites at the FUL locus under LDs. Abscisic acid (ABA) regulates stress responses such as the drought-escape response, and aspects of plant development, including axillary meristem growth and meristem arrest. The FD protein is phylogenetically closely related to bZIP transcription factors involved in ABA signalling; however, evidence for the involvement of FD in ABA signalling is weak. I disrupted ABA signalling specifically within the FD expression domain, which resulted in defects in plant shoot architecture under LDs. In legumes, FD paralogues mediate the floral transition but also determine inflorescence architecture. I identified HOMEOBOX PROTEIN 21 (HB-21), which is involved in ABA signalling, to be a direct downstream target of FD. The level of HB-21 mRNA was lower in fd than in wild-type inflorescences. The hb21 and fd mutants produced taller shoots with more siliques on the main shoot compared with wild type; thus, the regulation of HB-21 by FD links FD with inflorescence development in Arabidopsis potentially through ABA signalling. This PhD focuses on the bZIP transcription factor FD and how it regulates flowering time and inflorescence development in Arabidopsis. Collectively, the results show that FD functions throughout the Arabidopsis life cycle, and provide insight into the temporal FD-mediated transcriptional network at the SAM

Gastrointestinal stenting: Current status and imaging features

AbstractThe use of stents in the gastrointestinal tract has been subjected to major changes. Initially, the use of stents was restricted to malignant strictures in patients with metastatic disease. But thanks to reduction of the morbidity and mortality rates, they are now used with curative intention and in patients with benign diseases after careful selection. However, for patients presenting with colon obstruction due to an advanced colon carcinoma, the mortality and morbidity are still high. The purpose of this review is to provide an overview of indications, techniques and further developments of the stents in the gastrointestinal tract and to highlight the predominant role of multidetector row computed tomography (MDCT) in the detection of potential complications

Oxaliplatin use in pressurized intraperitoneal aerosol chemotherapy (PIPAC) is safe and effective: A multicenter study.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new drug delivery method used in patients with peritoneal cancer (PC) of primary or secondary origin. Intraperitoneal use of oxaliplatin raises concerns about toxicity, especially abdominal pain. The objective of this study was to assess the tolerance of PIPAC with oxaliplatin (PIPAC-Ox) in a large cohort of patients and to identify the risk factors for high grade toxicity, discontinuation of treatment and impaired survival. This retrospective cohort study included all consecutive patients treated with PIPAC-Ox (92 mg/m <sup>2</sup> ) in five centers specialized in the treatment of PC. The procedure was repeated every 6 weeks. Outcomes of interest were Common Terminology Criteria for Adverse Events (CTCAE), symptoms and survival (Kaplan-Meier). Univariate risk factors were included in a multinominal regression model to control for bias. Overall, 251 PIPAC-Ox treatments were performed in 101 patients (45 female) having unresectable PC of various origins: 66 colorectal, 15 gastric, 5 ovarian, 3 mesothelioma, 2 pseudomyxoma, 10 other malignancies (biliary, pancreatic, endocrine) respectively. The median PCI was 19 (IQR: 10-28). Postoperative abdominal pain was present in 23 patients. Out of the 9 patients with grade 3 abdominal pain, only 3 needed a change of PIPAC drug. CTCAE 4.0 toxicity grade 4 or higher was encountered in 16(15.9%) patients. The patients had a mean of 2.5 procedures/patient (SD = 1.5). 50 subjects presented with symptom improvement. Oxaliplatin-based PIPAC appears to be a safe treatment that offers good symptom control and promising survival for patients with advanced peritoneal disease

Intraperitoneal aerosolization of albumin-stabilized paclitaxel nanoparticles (Abraxane™) for peritoneal carcinomatosis : a phase I first-in-human study

Background: Nanoparticles hold considerable promise for aerosol-based intraperitoneal delivery in patients with carcinomatosis. Recently, results from preclinical and early clinical trials suggested that albumin-bound paclitaxel (ABP, Abraxane (TM)) may result in superior efficacy in the treatment of peritoneal metastases (PM) compared to the standard solvent-based paclitaxel formulation (Taxol (TM)). Here, we propose a phase I study of pressurized intraperitoneal aerosol chemotherapy (PIPAC) using ABP in patients with upper Gastrointestinal, breast, or ovarian cancer. Methods: Eligible patients with advanced, biopsy-proven PM from ovarian, breast, gastric, hepatobiliary, or pancreatic origin will undergo three PIPAC treatments using ABP with a 4-week interval. The dose of ABP will be escalated from 35 to 140 mg/m(2) using a Bayesian approach until the maximally tolerated dose is determined. The primary end point is dose-limiting toxicity. Secondary analyses include surgical morbidity, non-access rate, pharmacokinetic and pharmacodynamic analyses, quality of life, and exploratory circulating biomarker analyses. Discussion: ABP holds considerable promise for intraperitoneal aerosol delivery. The aim of this study is to determine the dose level for future randomized phase II trials using ABP in PIPAC therapy

Innovative Approaches to Analysing Carbon Sequestration as a Mitigation Strategy in Tropical Pasture Landscapes in Two Emblematic Contexts, the Amazon and the West African Sahel

The relationship between ruminant production systems and climate change is complex. As a major contributor to greenhouse gas (GHG) emissions, the sector has been the subject of considerable controversy, with particularly severe criticism in the 2000s. However, ten years ago, the attitude towards grazing lands began to change. Their efficient use of non-renewable energy and their contribution to carbon (C) sequestration were considered as key factors in the new environmental challenge. The reality of this mitigation potential was recently called into question once again in the global agriculture and climate change debate, including that of sequestration in the soil where grazing lands occupy a major position (30-40% of the land surface representing 30% of the soil organic C of the world). Few scientific references are available on these questions in tropical regions, and the standard metrics and methods used may turn out to be unsuitable for the correct evaluation of grazed ecosystems in these regions. Significant work is therefore required to establish baselines and design strategies to ensure sustainable grazing in these regions where the global sequestration potential is high relative to the surface areas concerned. To contribute to this debate, we focus on mitigation options offered by rangelands and grasslands and their management in two emblematic tropical contexts, humid and dry tropics, where field studies have been based on original and holistic approaches at different levels. In Amazonia, if curbing deforestation remains a priority, it needs to be accompanied by sustainable management of deforested areas. In the French Amazon (French Guiana), monitoring fields using chronosequences and flux towers has produced scientific knowledge on the significant mitigation capacities of grassland ecosystems. In the Brazilian Amazon, the spatial logic of the agro-ecological intensification of forage production has enabled a transition from individual extractive systems to farm management at communal levels. In the West African Sahelian region (Northern Senegal), an integrative study at landscape scale revealed the unexpected capacity of soil and shrubs for C sequestration that can offset the GHG emissions for which pastoralism in dry tropical zones is usually blamed

Radio-Frequency Plasma Polymerized Biodegradable Carrier for in vivo Release of Cis-Platinum

A low pressure plasma process based on plasma deposition has been used to develop a drug delivery strategy. In this study, a drug delivery system based on different layers of plasma co-polymerized Poly ε-caprolactone-Polyethylene glycol (PCL-PEG) co-polymers was deposited on biocompatible substrates. Cis-platinum (118 μgm/cm2) was used as an anti-cancer drug and incorporated for local delivery of the chemotherapeutic agent. The co-polymer layers and their interaction with cancer cells were analyzed by scanning electron microscopy. Our study showed that the plasma-PCL-PEG coated cellophane membranes, in which the drug, was included did not modify the flexibility and appearance of the membranes. This system was actively investigated as an alternative method of controlling localized delivery of drug in vivo. The loading of the anti-cancer drug was investigated by UV-VIS spectroscopy and its release from plasma deposited implants against BALB/c mice liver tissues were analyzed through histological examination and apoptosis by TUNEL assay. The histological examination of liver tissues revealed that when the plasma-modified membranes encapsulated the cis-platinum, the Glisson\u27s capsule and liver parenchyma were damaged. In all cases, inflammatory tissues and fibrosis cells were observed in contact zones between the implant and the liver parenchyma. In conclusion, low pressure plasma deposited uniform nano-layers of the co-polymers can be used for controlled release of the drug in vivo

Thrombopoietin Secretion by Human Ovarian Cancer Cells

The thrombopoietin (TPO) gene expression in human ovary and cancer cells from patients with ovarian carcinomatosis, as well as several cancer cell lines including MDA-MB231 (breast cancer), K562 and HL60 (Leukemic cells), OVCAR-3NIH and SKOV-3 (ovarian cancer), was performed using RT PCR, real-time PCR, and gene sequencing. Human liver tissues are used as controls. The presence of TPO in the cells and its regulation by activated protein C were explored by flow cytometry. TPO content of cell extract as well as plasma of a patient with ovarian cancer was evaluated by ELISA. The functionality of TPO was performed in coculture on the basis of the viability of a TPO-dependent cell line (Ba/F3), MTT assay, and Annexin-V labeling. As in liver, ovarian tissues and all cancer cells lines except the MDA-MB231 express the three TPO-1 (full length TPO), TPO-2 (12 bp deletion), and TPO-3 (116 pb deletion) variants. Primary ovarian cancer cells as well as cancer cell lines produce TPO. The thrombopoietin production by OVCAR-3 increased when cells are stimulated by aPC. OVCAR-3 cell’s supernatant can replace exogenous TPO and inhibited TPO-dependent cell line (Ba/F3) apoptosis. The thrombopoietin produced by tumor may have a direct effect on thrombocytosis/thrombosis occurrence in patients with ovarian cancer

Rosuvastatin Counteracts Vessel Arterialisation and Sinusoid Capillarisation, Reduces Tumour Growth, and Prolongs Survival in Murine Hepatocellular Carcinoma

Background and Aims. An arterial blood supply and phenotypic changes of the sinusoids characterise the liver vasculature in human hepatocellular carcinoma (HCC). We investigated the effects of rosuvastatin on liver vessel anomalies, tumour growth and survival in HCC. Methods. We treated transgenic mice developing HCC, characterized by vessel anomalies similar to those of human HCC, with rosuvastatin. Results. In the rosuvastatin group, the survival time was longer (P < .001), and liver weight (P < .01) and nodule surface (P < .01) were reduced. Rosuvastatin decreased the number of smooth muscle actin-positive arteries (P < .05) and prevented the sinusoid anomalies, with decreased laminin expression (P < .001), activated hepatic stellate cells (P < .001), and active Notch4 expression. Furthermore, rosuvastatin inhibited endothelial cell but not tumour hepatocyte functions. Conclusions. Rosuvastatin reduced the vessel anomalies and tumour growth and prolonged survival in HCC. These results represent new mechanisms of the effects of statin on tumour angiogenesis and a potential target therapy in HCC

Functional Divergence of the Arabidopsis Florigen-Interacting bZIP Transcription Factors FD and FDP.

Flowering of many plant species depends on interactions between basic leucine zipper (bZIP) transcription factors and systemically transported florigen proteins. Members of the genus Arabidopsis contain two of these bZIPs, FD and FDP, which we show have largely complementary expression patterns in shoot apices before and during flowering. CRISPR-Cas9-induced null mutants for FDP flower slightly earlier than wild-type, whereas fd mutants are late flowering. Identical G-box sequences are enriched at FD and FDP binding sites, but only FD binds to genes involved in flowering and only fd alters their transcription. However, both proteins bind to genes involved in responses to the phytohormone abscisic acid (ABA), which controls developmental and stress responses. Many of these genes are differentially expressed in both fd and fdp mutant seedlings, which also show reduced ABA sensitivity. Thus, florigen-interacting bZIPs have distinct functions in flowering dependent on their expression patterns and, at earlier stages in development, play common roles in phytohormone signaling