Consumption of Select Dietary Emulsifiers Exacerbates the Development of Spontaneous Intestinal Adenoma

Inflammation is a well-characterized critical driver of gastrointestinal cancers. Previous findings have shown that intestinal low-grade inflammation can be promoted by the consumption of select dietary emulsifiers, ubiquitous component of processed foods which alter the composition and function of the gut microbiota. Using a model of colitis-associated cancer, we previously reported that consumption of the dietary emulsifiers carboxymethylcellulose or polysorbate-80 exacerbated colonic tumor development. Here, we investigate the impact of dietary emulsifiers consumption on cancer initiation and progression in a genetical model of intestinal adenomas. In APC^min mice, we observed that dietary emulsifiers consumption enhanced small-intestine tumor development in a way that appeared to be independent of chronic intestinal inflammation but rather associated with emulsifiers’ impact on the proliferative status of the intestinal epithelium as well as on intestinal microbiota composition in both male and female mice. Overall, our findings further support the hypothesis that emulsifier consumption may be a new modifiable risk factor for colorectal cancer (CRC) and that alterations in host–microbiota interactions can favor gastrointestinal carcinogenesis in individuals with a genetical predisposition to such disorders.     

Argon Attenuates Multiorgan Failure in Relation with HMGB1 Inhibition

Argon inhalation attenuates multiorgan failure (MOF) after experimental ischemic injury. We hypothesized that this protection could involve decreased High Mobility Group Box 1 (HMGB1) systemic release. We investigated this issue in an animal model of MOF induced by aortic cross-clamping. Anesthetized rabbits were submitted to supra-coeliac aortic cross-clamping for 30 min, followed by 300 min of reperfusion. They were randomly divided into three groups (n = 7/group). The Control group inhaled nitrogen (70%) and oxygen (30%). The Argon group was exposed to a mixture of argon (70%) and oxygen (30%). The last group inhaled nitrogen/oxygen (70/30%) with an administration of the HMGB1 inhibitor glycyrrhizin (4 mg/kg i.v.) 5 min before aortic unclamping. At the end of follow-up, cardiac output was significantly higher in Argon and Glycyrrhizin vs. Control (60 ± 4 and 49 ± 4 vs. 33 ± 8 mL/kg/min, respectively). Metabolic acidosis was attenuated in Argon and Glycyrrhizin vs. Control, along with reduced amount of norepinephrine to reverse arterial hypotension. This was associated with reduced interleukin-6 and HMGB1 plasma concentration in Argon and Glycyrrhizin vs. Control. End-organ damages were also attenuated in the liver and kidney in Argon and Glycyrrhizin vs. Control, respectively. Argon inhalation reduced HMGB1 blood level after experimental aortic cross-clamping and provided similar benefits to direct HMGB1 inhibition.     

Tumor Suppressive Role of miR-342-5p in Human Chondrosarcoma Cells and 3D Organoids

Chondrosarcomas are malignant bone tumors. Their abundant cartilage-like extracellular matrix and their hypoxic microenvironment contribute to their resistance to chemotherapy and radiotherapy, and no effective therapy is currently available. MicroRNAs (miRNAs) may be an interesting alternative in the development of therapeutic options. Here, for the first time in chondrosarcoma cells, we carried out high-throughput functional screening using impedancemetry, and identified five miRNAs with potential antiproliferative or chemosensitive effects on SW1353 chondrosarcoma cells. The cytotoxic effects of miR-342-5p and miR-491-5p were confirmed on three chondrosarcoma cell lines, using functional validation under normoxia and hypoxia. Both miRNAs induced apoptosis and miR-342-5p also induced autophagy. Western blots and luciferase reporter assays identified for the first time Bcl-2 as a direct target of miR-342-5p, and also Bcl-xL as a direct target of both miR-342-5p and miR-491-5p in chondrosarcoma cells. MiR-491-5p also inhibited EGFR expression. Finally, only miR-342-5p induced cell death on a relevant 3D chondrosarcoma organoid model under hypoxia that mimics the in vivo microenvironment. Altogether, our results revealed the tumor suppressive activity of miR-342-5p, and to a lesser extent of miR-491-5p, on chondrosarcoma lines. Through this study, we also confirmed the potential of Bcl-2 family members as therapeutic targets in chondrosarcomas.     

Early Inactivation of Membrane Estrogen Receptor Alpha (ERα) Recapitulates the Endothelial Dysfunction of Aged Mouse Resistance Arteries

Flow-mediated dilation (FMD) of resistance arteries is essential for tissue perfusion but it decreases with ageing. As estrogen receptor alpha (Erα encoded by Esr1), and more precisely membrane ERα, plays an important role in FMD in young mice in a ligand-independent fashion, we evaluated its influence on this arteriolar function in ageing. We first confirmed that in young (6-month-old) mice, FMD of mesenteric resistance arteries was reduced in Esr1−/− (lacking ERα) and C451A-ERα (lacking membrane ERα). In old (24-month-old) mice, FMD was reduced in WT mice compared to young mice, whereas it was not further decreased in Esr1−/− and C451A-ERα mice. Markers of oxidative stress were similarly increased in old WT and C451A-ERα mice. Reduction in oxidative stress with superoxide dismutase plus catalase or Mito-tempo, which reduces mitochondrial superoxide restored FMD to a normal control level in young C451A-ERα mice as well as in old WT mice and old C451A-ERα mice. Estradiol-mediated dilation was absent in old WT mice. We conclude that oxidative stress is a key event in the decline of FMD, and that an early defect in membrane ERα recapitulates phenotypically and functionally ageing of these resistance arteries. The loss of this function could take part in vascular ageing.     

Phosphocatalytic Kinome Activity Profiling of Apoptotic and Ferroptotic Agents in Multiple Myeloma Cells

Through phosphorylation of their substrate proteins, protein kinases are crucial for transducing cellular signals and orchestrating biological processes, including cell death and survival. Recent studies have revealed that kinases are involved in ferroptosis, an iron-dependent mode of cell death associated with toxic lipid peroxidation. Given that ferroptosis is being explored as an alternative strategy to eliminate apoptosis-resistant tumor cells, further characterization of ferroptosis-dependent kinase changes might aid in identifying novel druggable targets for protein kinase inhibitors in the context of cancer treatment. To this end, we performed a phosphopeptidome based kinase activity profiling of glucocorticoid-resistant multiple myeloma cells treated with either the apoptosis inducer staurosporine (STS) or ferroptosis inducer RSL3 and compared their kinome activity signatures. Our data demonstrate that both cell death mechanisms inhibit the activity of kinases classified into the CMGC and AGC families, with STS showing a broader spectrum of serine/threonine kinase inhibition. In contrast, RSL3 targets a significant number of tyrosine kinases, including key players of the B-cell receptor signaling pathway. Remarkably, additional kinase profiling of the anti-cancer agent withaferin A revealed considerable overlap with ferroptosis and apoptosis kinome activity, explaining why withaferin A can induce mixed ferroptotic and apoptotic cell death features. Altogether, we show that apoptotic and ferroptotic cell death induce different kinase signaling changes and that kinome profiling might become a valid approach to identify cell death chemosensitization modalities of novel anti-cancer agents.     

A typical example of a photomagnetic study carried out on a spin-crossover material

The light-induced excited spin state trapping (LIESST) is a well known phenomenon in an iron(II) spin-crossover (SCO) material which offers some interesting prospects in data storage. In this work, we present a typical investigation of the photomagnetic properties of a SCO material. At the surface of the sample, the light-induced phenomenon is investigated by using a home-built reflectivity set up and in bulk material by using a quantum design SQUID magnetometer coupled to a light source.     

Platelet-derived growth factor expression in primary pulmonary hypertension: comparison of HIV seropositive and HIV seronegative patients

Primary pulmonary hypertension (PPH) is characterized by intimal fibrosis and cell proliferation (including fibroblasts, smooth muscle and endothelial cells) in the distal pulmonary arterial tree. Considerable interest has been generated by recent reports of PPH in human immunodeficiency virus (HIV)-1-infected individuals. Although the lack of evidence for a pulmonary artery infection has suggested that in such cases HIV may act through mediator release rather than by direct endothelial infection, the mechanisms underlying HIV-associated PPH remain poorly defined. Platelet-derived growth factor (PDGF) has the ability to induce smooth muscle cell and fibroblast proliferation and migration. Given these considerations, we have attempted to document a possible role for PDGF in PPH occurring in HIV seropositive and seronegative patients. Using semiquantitative polymerase chain reaction (PCR), PDGF A-chain messenger ribonucleic acid (mRNA) expression was analysed in surgical lung biopsies from 13 HIV seronegative patients and one HIV seropositive patient, all displaying severe PPH. In parallel, lung samples from two patients with HIV-1-associated PPH were studied by immunohistochemistry and in situ hybridization. Results were compared to those obtained in three HIV-1-infected individuals with no pulmonary complication (as demonstrated by clinical, radiological, bacteriological, and necropsy findings) and five control lung biopsies. As compared to controls, PDGF A-chain mRNA expression is elevated in lung biopsies from patients displaying PPH (p=0.029). In HIV-1-associated PPH, interstitial perivascular cells expressing PDGF A-chain mRNA and protein could be detected by in situ hybridization and immunohistochemistry, respectively. Platelet-derived growth factor expression is elevated in lung biopsies of patients displaying primary pulmonary hypertension. Growth factors such as platelet-derived growth factor may play a part in the initiation and/or progression of primary pulmonary hypertension.     

Therapists' emotional reactions to substance abusers: A new questionnaire and initial findings.

Developed and tested the Ratings of Emotional Attitudes to Clients by Treaters (REACT) scale. The REACT was administered to 52 therapists and 140 cocaine-dependent outpatients, at sessions 2, 5, and 24 of psychotherapy. It was found to have high internal consistency at each time point, moderately high convergent validity with therapists' (but not patients') therapeutic alliance ratings, and a factor structure that appeared to meaningfully derive 4 factors: "therapist in conflict with self," "therapist focused on own needs," "positive connection," and "therapist in conflict with the patient." Therapists' emotional responses were found to become more negative over the course of treatment, and, when compared by theoretical orientation, were found more positive for 12-step drug counselors than for cognitive or supportive-expressive therapists. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Thematic relations in adults' concepts.

Concepts can be organized by their members' similarities, forming a kind (e.g., animal), or by their external relations within scenes or events (e.g., cake and candles). This latter type of relation, known as the thematic relation, is frequently found to be the basis of children's but not adults' classification. However, 10 experiments found that when thematic relations are meaningful and salient, they have significant influence on adults' category construction (sorting), inductive reasoning, and verification of category membership. The authors conclude that concepts function closely with knowledge of scenes and events and that this knowledge has a role in adults' conceptual representations. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

EUA and sCER phase II price drivers: Unveiling the reasons for the existence of the EUA–sCER spread

This article studies the price relationships between EU emissions allowances (EUAs) – valid under the EU Emissions Trading Scheme (EU ETS) – and secondary Certified Emissions Reductions (sCERs)—established from primary CERs generated through the Kyoto Protocol's Clean Development Mechanism (CDM). Given the price differences between EUAs and sCERs, financial and industrial operators may benefit from arbitrage strategies by buying sCERs and selling EUAs (i.e. selling the EUA–sCER spread) to cover their compliance position as industrial operators are allowed to use sCERs towards compliance with their emissions cap within the European system up to 13.4%. Our central results show that the spread is mainly driven by EUA prices and market microstructure variables and less importantly, as we would expect, by emissions-related fundamental drivers. This might be justified by the fact that the EU ETS remains the greatest source of CER demand to date.