Variations of ornithine decarboxylase activity and S-adenosyl-L-methionine and 5'-methylthioadenosine contents during the development of diethylnitrosamine-induced liver hyperplastic nodules and hepatocellular carcinoma

Liver ornithine decarboxylase (ODC) activity and content ofS-adenosyl-L-methionine (SAM) and its catabolite 5'-methyl-thioadenosine(5'-MTA) were determined in the late stages of hepatocarcinogenesis.Wistar rats received one diethyl-nitrosamine dose, followedby a partial hepatectomy at the midpoint of a 15-day treatmentwith 2-acetylaminofluorene (2-AAF), and then by an 18-week phenobarbital(PB) treatment. Thirty-eight per cent of liver was -glutamyltranspeptidase(GGT)-positive and no visible nodules and hepatocellular carcinomasdeveloped 16 weeks after starting 2-AAF feeding. Hyperplasticnodules and hepatocellular carcinomas were found on weeks 24and 56 respectively. On weeks 24 and 56 only 10% of liver wasoccupied by GGT-positive foci. At all times studied the fociexhibited a low labeling index (LI), and liver ODC activitywas near control values. By contrast, a high ODC activity andLI and a low SAM and 5'-MTA levels were found in hyperplasticnodules and neoplasia. These tissues exhibited a high 5'-MTAphosphorylase activity. SAM administration during PB treatment,caused a 25–36% fall of GGT-positive liver and preventedthe development of hyperplastic nodules and hepatocellular carcinomas.This was coupled to a sharp increase of SAM and 5'-MTA livercontents. SAM and 5'-MTA inhibited hepatocyte DNA synthesisin vitro. The addition of 5'-MTA to the reaction mixture forthe ODC assay strongly inhibited ODC activity. However, thepreincubation of SAM with liver homogenates or hepatocytes,used to prepare crude ODC, was necessary to inhibit ODC activityby SAM. Adenine, an inhibitor of 5'-MTA-phosphorylase, enhancedinhibition of DNA synthesis and ODC activity by SAM and 5'-MTA.Thus, during a prolonged promoting treatment a selected populationof GGT-positive foci appears to acquire a stable phenotype characterizedby a high DNA and polyamine synthesis. The development of nodulesand carcinomas is associated with low SAM and 5'-MTA contentsand high ODC activity and LI. 5'-MTA accumulation, during SAMadministration, is probably responsible for the inhibition ofpromotion by SAM.     

Successful extracorporeal membrane oxygenation transport of a 4‐month‐old brain‐dead infant for organ donation: A case report

A 4‐month‐old infant was declared brain‐dead 2 days after being initiated on venoarterial ECMO for a refractory septic shock. All brain death diagnostic criteria were fulfilled according to French law, and parental consent was given for organ donation. The hospital where ECMO was initiated had no authorization for organ procurement, and the donor was then transferred to the local referral center for child organ recovery with our mobile ECMO team to maintain organ perfusion. The kidneys were recovered and successfully transplanted to a child who is now well and alive. Although the transport elements of this case report are of limited relevance to an international audience as no other country, to our knowledge, has this particular organization, it does show excellent collaboration between teams to realize the goal of organ donation for this family. This is the first case describing a successful inter‐hospital transport for organ procurement of a brain‐dead infant on ECMO. Brain‐dead pediatric patients undergoing ECMO can be considered as potential organ donors to expand the donor pool.     

Talking About Sexuality in the Context of Rehabilitation Following Traumatic Brain Injury: An Integrative Review of Operational Aspects

Sexuality and Disability - An integrative review of the literature reporting operational aspects (how, when, who, with what) of rehabilitation professionals’ discussion of sexuality with...     

Active Nanomaterials to Meet the Challenge of Dental Pulp Regeneration

The vitality of the pulp is fundamental to the functional life of the tooth. For this aim, active and living biomaterials are required to avoid the current drastic treatment, which is the removal of all the cellular and molecular content regardless of its regenerative potential. The regeneration of the pulp tissue is the dream of many generations of dental surgeons and will revolutionize clinical practices. Recently, the potential of the regenerative medicine field suggests that it would be possible to achieve such complex regeneration. Indeed, three crucial steps are needed: the control of infection and inflammation and the regeneration of lost pulp tissues. For regenerative medicine, in particular for dental pulp regeneration, the use of nano-structured biomaterials becomes decisive. Nano-designed materials allow the concentration of many different functions in a small volume, the increase in the quality of targeting, as well as the control of cost and delivery of active molecules. Nanomaterials based on extracellular mimetic nanostructure and functionalized with multi-active therapeutics appear essential to reverse infection and inflammation and concomitantly to orchestrate pulp cell colonization and differentiation. This novel generation of nanomaterials seems very promising to meet the challenge of the complex dental pulp regeneration.     

Evaluation of the GADD45α‐GFP GreenScreen HC assay for rapid and reliable in vitro early genotoxicity screening

Twenty‐two of Galderma's proprietary compounds were tested in the GADD45α‐GFP ‘GreenScreen HC’ assay (GS), the SOS‐ChromoTest and the Mini‐Ames to evaluate GSs performance for early genotoxicity screening purposes. Forty more characterized compounds were also tested, including antibiotics: metronidazole, clindamycin, tetracycline, lymecycline and neomycin; and catecholamines: resorcinol mequinol, hydroquinone, one aneugen carbendazim, one corticoid dexamethasone, one peroxisome proliferator‐activated receptor rosiglitazone, one pesticide carbaryl and two further proprietary molecules with in vitro genotoxicity data. With proprietary molecules, this study concluded that the GS renders the SOS‐ChromoTest obsolete for in vitro screening. The GS confirmed all results of the Mini‐Ames test (100% concordance). Compared with the micronucleus test, the GS showed a concordance of 82%. With known compounds, the GS ranked the potency of positive results for catecholamines in accordance with other genotoxicity tests and showed very reproducible results. It confirmed positive results for carbendazim, for tetracycline antibiotics and for carbaryl. The GS produced negative results for metronidazole, a nitroreduction‐specific bacterial mutagen, for dexamethasone (a non‐genotoxic apoptosis inducer), for rosiglitazone (a GADD45γ promoter inducer) and for clindamycin and neomycin (inhibitors of macromolecular synthesis in bacteria). As such, the GS appears to be a reproducible, robust, specific and sensitive test for genotoxicity screening. Copyright © 2012 John Wiley & Sons, Ltd.     

Efficacy of Immune Checkpoint Inhibitors in KRAS-Mutant Non-Small Cell Lung Cancer (NSCLC)

IntroductionKRAS mutation is the most frequent molecular alteration found in advanced NSCLC; it is associated with a poor prognosis without available targeted therapy. Treatment options for NSCLC have been recently enriched by the development of immune checkpoint inhibitors (ICIs), and data about its efficacy in patients with KRAS-mutant NSCLC are discordant. This study assessed the routine efficacy of ICIs in advanced KRAS-mutant NSCLC.MethodsIn this retrospective study, clinical data were extracted from the medical records of patients with advanced NSCLC treated with ICIs and with available molecular analysis between April 2013 and June 2017. Analysis of programmed death ligand 1 (PD-L1) expression was performed if exploitable tumor material was available.ResultsA total of 282 patients with ICI-treated (in the first line or more) advanced NSCLC (all histological subgroups) who were treated with ICIs (anti–programmed death 1, anti–PD-L1, or anti–cytotoxic T-lymphocyte associated protein 4 antibodies), including 162 (57.4%) with KRAS mutation, 27 (9.6%) with other mutations, and 93 (33%) with a wild-type phenotype, were identified. PD-L1 analysis was available for 128 patients (45.4%), of whom 45.3% and 19.5% had PD-L1 expression of 1% or more and 50%, respectively (49.5% and 21.2%, respectively, in the case of the 85 patients with KRAS-mutant NSCLC). No significant difference was seen in terms of objective response rates, progression-free survival, or overall survival between KRAS-mutant NSCLC and other NSCLC. No significant differences in overall survival or progression-free survival were observed between the major KRAS mutation subtypes (G12A, G12C, G12D, G12V, and G13C). In KRAS-mutant NSCLC, unlike in non–KRAS-mutant NSCLC, the efficacy of ICIs is consistently higher, even though not statistically significant, for patients with PD-L1 expression in 1% or more of tumor cells than for those with PD-L1 expression in less than 1% of tumor cells, and this finding is especially true when PD-L1 expression is high (PD-L1 expression ≥50%).ConclusionFor patients with KRAS-mutant NSCLC (all mutational subtypes), the efficacy of ICI is similar to that for patients with other types of NSCLC. PD-L1 expression seems to be more relevant for predicting the efficacy of ICIs in KRAS-mutant NSCLC than it is in other types of NSCLC.