Plk4 is required for cytokinesis and maintenance of chromosomal stability

Aneuploidy is a characteristic feature of established cancers and can promote tumor development. Aneuploidy may arise directly, through unequal distribution of chromosomes into daughter cells, or indirectly, through a tetraploid intermediate. The polo family kinase Plk4/Sak is required for late mitotic progression and is haploinsufficient for tumor suppression in mice. Here we show that loss of heterozygosity (LOH) occurs at the Plk4 locus in 50% of human hepatocellular carcinomas (HCC) and is present even in preneoplastic cirrhotic liver nodules. LOH at Plk4 is associated with reduced Plk4 expression in HCC tumors but not with mutations in the remaining allele. Plk4^+/− murine embryonic fibroblasts (MEFs) at early passage show a high incidence of multinucleation, supernumerary centrosomes, and a near-tetraploid karyotype. Underlying these phenotypes is a high rate of primary cytokinesis failure, associated with aberrant actomyosin ring formation, reduced RhoA activation, and failure to localize the RhoA guanine nucleotide exchange factor Ect2 to the spindle midbody. We further show that Plk4 normally localizes to the midbody and binds to and phosphorylates Ect2 in vitro. With serial passaging Plk4^+/− MEFs rapidly immortalize, acquiring an increasing burden of nonclonal and clonal gross chromosomal irregularities, and form tumors in vivo. Our results indicate that haploid levels of Plk4 disrupt RhoGTPase function during cytokinesis, resulting in aneuploidy and tumorigenesis, thus implicating early LOH at Plk4 as one of the drivers of human hepatocellular carcinogenesis. These findings represent an advance in our understanding of genetic predisposition to HCC, which continues to increase in incidence globally and particularly in North America.     

Essential oils composition in two Rosmarinus officinalis L. varieties and incidence for antimicrobial and antioxidant activities

The essential oil composition of Rosmarinus officinalis var. typicus and var. troglodytorum endemic to Tunisia, and growing wild in different bioclimates, was determined by GC and GC–MS. Oils were assessed for their antimicrobial and antioxidant activity. A variation of the chemical composition attributed to varieties rather than to bioclimates was revealed. 1.8-Cineole (47.2–27.5%) and camphor (12.9–27.9%) were identified as the main constituents of var. typicus and var. troglodytorum, respectively. The principal component analysis performed on oil constituents for all the populations allowed the distinction of two distinct population groups in accordance to the varietal subdivision. Based on the determination of the diameter of inhibition and the determination of the minimum inhibitory concentration, a low to moderate antimicrobial activity according to oils was revealed against eight bacteria tested. However, oils from var. troglodytorum showed higher bactericidal effect than those from var. typicus. The oils’ antioxidant activity, determined by 1,1-diphenyl-1-picrylhydrazyl (DPPH) assay, ferric reducing (FRAP) assay and β-carotene bleaching test, was relatively high. The highest activity was found in oils from var. troglodytorum and in one population of var. typicus from the upper semi-arid bioclimate.     

Medical certificate in psychiatry: practical aspects

Among certificates written in psychiatry, some are obligatory, admission certificate, in case of automatically hospitalization or that asked by a third party, certificate of 48 hours: in which the psychiatrist of the admission' service describes the state of the patient and indicates the necessity or not to continue the hospitalization, monthly certificate: to justify the maintenance of hospitalization or to ask its end and certificate of situation be written in some particular circumstances. Others concern the cases of expert appraisement (in civilian or penal rights) or in the framework of medical controls asked by the employer. Other certificates are optional or customary. They could be delivered if asked by the patient. These considerations incite to follow scrupulously ethical rules and common sense when doing these certificates. Finally, The certificate has always to be given to the patient personally. That will be mentioned down of the document.     

Systemic effects of epidural and intra-articular glucocorticoid injections in diabetic and non-diabetic patients

IntroductionWhereas the systemic effects of glucocorticoid therapy have been extensively reported, little is known about those of local glucocorticoid injections. The objective of this study was to look for systemic effects of local glucocorticoid injections at two sites in diabetic and non-diabetic patients.MethodsWe studied 29 patients (18 women and 11 men with an age range of 18–86 years). The injection site was the epidural space in 18 patients (4 with and 14 without diabetes) with disk-related sciatica and the shoulder in 11 patients (8 with and 3 without diabetes) with frozen shoulder. Each patient was given three injections of 1.5 ml cortivazol (5.625 mg of cortivazol or about 85 mg prednisone-equivalent per injection and about 250 mg prednisone-equivalent in all), at 3-day intervals. Of the 12 patients with diabetes, 2 were on insulin therapy. At baseline and at the post-treatment visits 1, 7, and 21 days after the third injection, the following tests were done: plasma cortisol and ACTH at 8 am, urinary free cortisol excretion in 24 hours, fasting and postprandial blood glucose, serum cholesterol and triglycerides, and serum sodium and potassium. Blood pressure was measured at each visit.ResultsMean systolic blood pressure increased significantly between baseline (123 ± 10 mmHg) and the first two post-treatment visits (day 1, 127 ± 9 mmHg; and day 7, 128 ± 10 mmHg) but returned to baseline values by the third post-treatment visit (day 21). Mean postprandial blood glucose was significantly higher at the day 1 post-treatment visit (10.1 ± 5.4 mmol/l) than at baseline (7.5 ± 2.9 mmol/l). At the day 7 post-treatment visit, blood glucose remained significantly elevated compared to baseline in the 12 diabetic patients (13.9 ± 4.8 mmol/l versus 9.4 ± 3.3 mmol/l at baseline). In both the overall population and the various subgroups, plasma cortisol and ACTH and urinary free cortisol were markedly reduced at the day 1 and day 7 post-treatment visits, compared to baseline. At the day 21 visit, these variables were diminished in the group given epidural injections, whereas plasma cortisol and ACTH were normal in the group treated intra-articularly. No significant variations were noted for fasting blood glucose or for serum levels of cholesterol, triglycerides, sodium, and potassium.ConclusionThe administration of three local cortivazol injections was followed by suppression of the corticotropic axis that persisted beyond 21 days after epidural injection and recovered more rapidly after intra-articular injection. Systolic blood pressure increased transiently. Elevations in postprandial glucose levels lasted longer in diabetic than non-diabetic patients.     

The presence of wild type p53 in hematological cancers improves the efficacy of combinational therapy targeting metabolism

Manipulation of metabolic pathways in hematological cancers has therapeutic potential. Here, we determined the molecular mechanism of action of the metabolic modulator dichloroacetate (DCA) in leukemic cells. We found that DCA induces the AMP-activated protein kinase (AMPK)/p53 pathway with increased efficacy in tumors expressing wild type (wt p53). Clinically relevant, low concentrations of doxorubicin synergize in vitro and in vivo with DCA to further enhance p53 activation and to block tumor progression. Leukemia cell lines and primary leukemic cells containing mutant p53 are resistant to the above-described combination approach. However, DCA synergized with the Hsp90 inhibitor 17-AAG to specifically eliminate these cells. Our studies strongly indicate that depending on the p53 status, different combination therapies would provide better treatment with decreased side effects in hematological cancers.     

Containment of Local COVID-19 Outbreak Among Hematopoietic Stem Cell Transplant Recipients and Healthcare Workers in a Pediatric Stem Cell Unit

Journal of Clinical Immunology -