Description: Although most deoxyribonucleic acid (DNA) lesions are accurately repaired before replication, replication across unrepaired lesions is the main source of point mutations. The lesion tolerance processes, which allow damaged DNA to be replicated, entail two branches, error-prone translesion synthesis (TLS) and error-free damage avoidance (DA). While TLS pathways are reasonably well established, DA pathways are poorly understood. The fate of a replication-blocking lesion is generally explored by means of plasmid-based assays. Although such assays represent efficient tools to analyse TLS, we show here that plasmid-borne lesions are inappropriate models to study DA pathways due to extensive replication fork uncoupling. This observation prompted us to develop a method to graft, site-specifically, a single lesion in the genome of a living cell. With this novel assay, we show that in Escherichia coli DA events massively outweigh TLS events and that in contrast to plasmid, chromosome-borne lesions partially require RecA for tolerance.

Description: Background:  Even though efficacy of biologics has been extensively studied in psoriasis vulgaris, studies in erythrodermic psoriasis, the most severe form of the disease, have beenscarcelyreported. Objectives:  To address the efficacy and safety of biologics in patients with erythrodermic psoriasis. Methods:  A multicentre national retrospective study was performed using the French Psoriasis Group network. Patients showing psoriasis involving at least 90% of body surface area (BSA), and in whom severity of the disease had been evaluated before and after 3 and/or 6 months of treatment with biologics, were enrolled in the study. Results were expressed using intention to treat analysis. Results:  We included 28 patients, representing 42 flares of erythrodermic psoriasis treated with infliximab (n=24), adalimumab (7), etanercept (6), ustekinumab (3) or efalizumab (2). A 75% improvement of BSA or PASI index 12 to 14 weeks after treatment onset was reached in 48% of flares treated with infliximab, in 50% of those treated with adalimumab and in 40% of those treated with etanercept. Twelve serious adverse events consisting of bacterial infection in 7 of them were observed. Biological treatment was discontinued for safety concern in 19% of cases. A given biologic was pursued up to 48 weeks in 34% of flares. Conclusion:  Biologics show overall good short-term efficacy, but treatment switch due to lack of efficacy or side effects is frequently observed on a longer term, with one third of patients still receiving the drug after one year. The most significant safety concern consists of severe infections.

Description: The Journal of Physical Chemistry B DOI: 10.1021/jp209800u

Description: Background:  Even though efficacy of biologics has been extensively studied in psoriasis vulgaris, studies in erythrodermic psoriasis, the most severe form of the disease, have beenscarcelyreported. Objectives:  To address the efficacy and safety of biologics in patients with erythrodermic psoriasis. Methods:  A multicentre national retrospective study was performed using the French Psoriasis Group network. Patients showing psoriasis involving at least 90% of body surface area (BSA), and in whom severity of the disease had been evaluated before and after 3 and/or 6 months of treatment with biologics, were enrolled in the study. Results were expressed using intention to treat analysis. Results:  We included 28 patients, representing 42 flares of erythrodermic psoriasis treated with infliximab (n=24), adalimumab (7), etanercept (6), ustekinumab (3) or efalizumab (2). A 75% improvement of BSA or PASI index 12 to 14 weeks after treatment onset was reached in 48% of flares treated with infliximab, in 50% of those treated with adalimumab and in 40% of those treated with etanercept. Twelve serious adverse events consisting of bacterial infection in 7 of them were observed. Biological treatment was discontinued for safety concern in 19% of cases. A given biologic was pursued up to 48 weeks in 34% of flares. Conclusion:  Biologics show overall good short-term efficacy, but treatment switch due to lack of efficacy or side effects is frequently observed on a longer term, with one third of patients still receiving the drug after one year. The most significant safety concern consists of severe infections.

Description: The immune contexture in human tumours: impact on clinical outcome Nature Reviews Cancer 12, 298 (2012). doi:10.1038/nrc3245 Authors: Wolf Herman Fridman, Franck Pagès, Catherine Sautès-Fridman & Jérôme Galon Tumours grow within an intricate network of epithelial cells, vascular and lymphatic vessels, cytokines and chemokines, and infiltrating immune cells. Different types of infiltrating immune cells have different effects on tumour progression, which can vary according to cancer type. In this Opinion article we discuss

Description: Biochemistry DOI: 10.1021/bi301398j

Description: Background: The present work was designed to evaluate the antibacterial properties of the methanol extracts of eleven selected Cameroonian spices on multi-drug resistant bacteria (MDR), and their ability to potentiate the effect of some common antibiotics used in therapy. Results: The extract of Cinnamomum zeylanicu against Escherichia coli ATCC 8739 and AG100 strains showed the best activities, with the lowest minimal inhibitory concentration (MIC) of 64 ¿g/ml. The extract of Dorstenia psilurus was the most active when tested in the presence of an efflux pump inhibitor, phenylalanine Arginine-ß- Naphtylamide (PAßN), a synergistic effect being observed in 56.25 % of the tested bacteria when it was combined with Erythromycin (ERY). Conclusion: The present work evidently provides information on the role of some Cameroonian spices in the fight against multi-resistant bacteria.

Description: Bacteria use the global bipolarization of their chromosomes into replichores to control the dynamics and segregation of their genome during the cell cycle. This involves the control of protein activities by recognition of specific short DNA motifs whose orientation along the chromosome is highly skewed. The KOPS motifs act in chromosome segregation by orienting the activity of the FtsK DNA translocase towards the terminal replichore junction. KOPS motifs have been identified in -Proteobacteria and in Bacillus subtilis as closely related G-rich octamers. We have identified the KOPS motif of Lactococcus lactis , a model bacteria of the Streptococcaceae family harbouring a compact and low GC% genome. This motif, 5'-GAAGAAG-3, was predicted in silico using the occurrence and skew characteristics of known KOPS motifs. We show that it is specifically recognized by L. lactis FtsK in vitro and controls its activity in vivo . L. lactis KOPS is thus an A-rich heptamer motif. Our results show that KOPS-controlled chromosome segregation is conserved in Streptococcaceae but that KOPS may show important variation in sequence and length between bacterial families. This suggests that FtsK adapts to its host genome by selecting motifs with convenient occurrence frequencies and orientation skews to orient its activity.

Description: Purpose: To retrospectively review the causes of false-negative results on prior magnetic resonance (MR) imaging studies in patients who developed breast cancer as revealed on a follow-up MR imaging study and to determine the presumptive causes of these false-negative findings. Materials and Methods: Fifty-eight pairs of MR imaging studies from one institution were assessed, consisting of a prior study without a diagnosis of cancer and a diagnostic study with subsequent findings of 60 cancers in 58 women at MR imaging (mean interval between prior and diagnostic MR examinations, 13.8 months). Two radiologists reviewed in consensus, in a nonblinded fashion, each pair of MR studies, comparing the diagnostic and the prior MR imaging studies to evaluate the rate of false-negative findings. The prospective reports were then analyzed to classify false-negatives findings in breast enhancement of breast cancers not identified at the time of imaging, potentially misinterpreted, and mismanaged. False-negative results on prior MR studies were retrospectively reassessed to identify possibly reasons why cancers had been not recognized, potentially misinterpreted, or mismanaged. Results: Twenty-eight (47% [95% confidence interval {CI}: 34%, 59%]) of the 60 cancers were retrospectively diagnosed as Breast Imaging Reporting and Data System grade 3, 4, or 5 lesions. Analysis of the prospective reports showed that six lesions (10% [95% CI: 2%, 18%]) had been not identified at the time of diagnosis, 15 lesions (25% [95% CI: 14%, 36%]) were potentially misinterpreted, and seven lesions (12% [95% CI: 3%, 20%]) were mismanaged. The main causes of misinterpretation were smooth margins of a mass ( n = 4), stability in size ( n = 3), and location of a nonmass in a postsurgical area ( n = 5). Mismanagement was mainly due to inadequate correlations between MR imaging and ultrasonographic (US) features, with inaccurate sampling with US guidance in five cases. Conclusion: In patients with breast cancer seen at MR imaging, retrospective evaluation of the prior MR imaging studies showed potential observer error in 47% of cases, resulting more from misinterpretation than from nonrecognition or mismanagement of cancers. © RSNA, 2012

Description: Effective immune responses depend upon appropriate T cell differentiation in accord with the nature of an infectious agent, and the contingency of differentiation depends minimally on TCR, coreceptor, and cytokine signals. In this reverse genetic study, we show that the MAPK Erk2 is not essential for T cell proliferation in the presence of optimum costimulation. Instead, it has opposite effects on T-bet and Gata3 expression and, hence, on Th1 and Th2 differentiation. Alternatively, in the presence of TGF-β, the Erk pathway suppresses a large program of gene expression, effectively limiting the differentiation of Foxp3 + regulatory T cells. In the latter case, the mechanisms involved include suppression of Gata3 and Foxp3 , induction of Tbx21 , phosphorylation of Smad2,3, and possibly suppression of Socs2, a positive inducer of Stat5 signaling. Consequently, loss of Erk2 severely impeded Th1 differentiation while enhancing the development of Foxp3 + -induced T regulatory cells. Selected profiles of gene expression under multiple conditions of T cell activation illustrate the opposing consequences of Erk pathway signaling.