DNA polymerase θ up-regulation is associated with poor survival in breast cancer,perturbs DNA replication,and promotes genetic instability

“Replicative stress” is one of the main factors underlying neoplasia from its early stages. Genes involved in DNA synthesis may therefore represent an underexplored source of potential prognostic markers for cancer. To this aim, we generated gene expression profiles from two independent cohorts (France, n = 206; United Kingdom, n = 117) of patients with previously untreated primary breast cancers. We report here that among the 13 human nuclear DNA polymerase genes, DNA Polymerase θ (POLQ) is the only one significantly up-regulated in breast cancer compared with normal breast tissues. Importantly, POLQ up-regulation significantly correlates with poor clinical outcome (4.3-fold increased risk of death in patients with high POLQ expression), and this correlation is independent of Cyclin E expression or the number of positive nodes, which are currently considered as markers for poor outcome. POLQ expression provides thus an additional indicator for the survival outcome of patients with high Cyclin E tumor expression or high number of positive lymph nodes. Furthermore, to decipher the molecular consequences of POLQ up-regulation in breast cancer, we generated human MRC5-SV cell lines that stably overexpress POLQ. Strong POLQ expression was directly associated with defective DNA replication fork progression and chromosomal damage. Therefore, POLQ overexpression may be a promising genetic instability and prognostic marker for breast cancer.     

INAUGURAL ARTICLE by a Recently Elected Academy Member:B-cell signaling networks reveal a negative prognostic human lymphoma cell subset that emerges during tumor progression

Human tumors contain populations of both cancerous and host immune cells whose malignant signaling interactions may define each patient''s disease trajectory. We used multiplexed phospho-flow cytometry to profile single cells within human follicular lymphoma tumors and discovered a subpopulation of lymphoma cells with impaired B cell antigen receptor (BCR) signaling. The abundance of BCR-insensitive cells in each tumor negatively correlated with overall patient survival. These lymphoma negative prognostic (LNP) cells increased as tumors relapsed following chemotherapy. Loss of antigen receptor expression did not explain the absence of BCR signaling in LNP tumor cells, and other signaling responses were intact in these cells. Furthermore, BCR signaling responses could be reactivated in LNP cells, indicating that BCR signaling is not missing but rather specifically suppressed. LNP cells were also associated with changes to signaling interactions in the tumor microenvironment. Lower IL-7 signaling in tumor infiltrating T cells was observed in tumors with high LNP cell counts. The strength of signaling through T cell mediator of B cell function CD40 also stratified patient survival, particularly for those whose tumors contained few LNP cells. Thus, analysis of cell–cell interactions in heterogeneous primary tumors using signaling network profiles can identify and mechanistically define new populations of rare and clinically significant cells. Both the existence of these LNP cells and their aberrant signaling profiles provide targets for new therapies for follicular lymphoma.     

Enhanced EEG functional connectivity in mesial temporal lobe epilepsy

PURPOSE: To analyze and compare spectral properties and interdependencies of intracerebral EEG signals recorded during interictal periods from mesial temporal lobe structures in two groups of epileptic patients defined according to the involvement of these structures in the epileptogenic zone (EZ). METHODS: Interictal EEG activity in mesial temporal lobe (MTL) structures (hippocampus, entorhinal cortex and amygdala) was obtained from intracerebral recordings performed in 21 patients with drug-resistant mesial temporal lobe epilepsy (MTLE group). This group was compared with a "control" group of patients (non-MTLE group) in whom depth-EEG recordings of MTL show that seizures did not start from the MTL. Comparison criteria were based on spectral properties and statistical coupling (nonlinear correlation coefficient h(2)) of MTL signals. RESULTS: Power spectral density analysis showed a significant decrease in the theta frequency sub-band (p=0.01) in the MTLE group. Nonlinear correlation (h(2)) values were found to be higher in the MTLE group than in the NMTLE group (p=0.0014). This effect was significant for theta, alpha, beta and gamma frequencies. Correlation values were not correlated with the frequency of interictal spikes (IS) and significant differences between groups were still measureable even when spikes were suppressed from analyzed EEG periods. DISCUSSION: This study shows that, during the interictal state, the EZ in MTLE is characterized by a decrease of oscillations in the theta sub-band and by a general increase of signal interdependencies. This last finding suggests that the EZ is characterized by network of neuronal assemblies with a reinforced functional connectivity.     

Population pharmacokinetics of the novel anticancer agent E7070 during four phase I studies: model building and validation.

PURPOSE: N-(3-Chloro-7-indolyl)-1,4-benzenedisulfonamide (E7070) is a novel sulfonamide anticancer agent currently in phase II clinical development for the treatment of solid tumors. Four phase I studies have been finalized, with E7070 administered at four different treatment schedules to identify the maximum-tolerated dose and the dose-limiting toxicities. Pharmacokinetic analyses of all studies revealed E7070 to have nonlinear pharmacokinetics. A population pharmacokinetic model was designed and validated to describe the pharmacokinetics of E7070 at all four treatment schedules and to identify the possible influences of patient characteristics on the pharmacokinetic parameters. PATIENTS AND METHODS: Plasma concentration-time data of all patients (n = 143) were fitted to several pharmacokinetic models using NONMEM. Seventeen covariables were investigated for their relation with individual pharmacokinetic parameters. A bootstrap procedure was performed to check the validity of the model. RESULTS: The data were best described using a three-compartment model with nonlinear distribution to a peripheral compartment and two parallel pathways of elimination from the central compartment: a linear and a saturable pathway. Body-surface area (BSA) was significantly correlated to both the volume of distribution of the central compartment and to the maximal elimination capacity. The fits of 500 bootstrap replicates of the data set demonstrated the robustness of the developed population pharmacokinetic model. CONCLUSION: A population pharmacokinetic model has been designed and validated that accurately describes the data of four phase I studies with E7070. Furthermore, it has been demonstrated that BSA-guided dosing for E7070 is important.     

Seroepidemiologische Studie zur Überwachung der Diphtherie-Immunität und Diphtherie-Schutz-impfung im Freistaat Sachsen 1996

Zusammenfassung  1996 wurden zur Beurteilung der Immunit?tslage der s?chsischen Bev?lkerung gegen Diphtherie 1378 Seren von Personen untersichiedlichen Alters im Zellkulturtest nach Miyamura auf neutralisierende Diphtherie-Antitoxingehalte untersucht (immunit?tskataster). An 203 Personen, bei denen eine Indikation zur Wiederimpfung vorlag, wurde die Boosterf?higkeit in Abh?ngigkeit von der dokumentierten Grundimmunisierung, der Anzahl der Widerimpfungen und nach dem Abstand zur letzten Impfung mit der gleichen Methodik beurteilt. Die Erfassung der diesbezüglich notwendigen personenbezogenen Angaben, die Serumgewinnung und Impfdurchführung erfolgte durch die Gesundheits?mter nach einem vorgegebenen Programm. Die Immunit?tslage der Bev?lkerung Sachsens, wohl stellvertretend für alle neuen Bundesl?nder, ist dank der 1961–1990 praktizierten Pflichtimpfung 1996 insgesamt noch mit ausreichend gut zu bewerten: 70% waren sicher, 17,7% relativ und nur 12,3% nicht geschützt. Unbefriedigend ist die Immunit?tslage bei den über, 40j?hrigen. Eine Boosterf?higkeit ist in Abh?ngigkeit von der dokumentierten Grundimmunisierung unterschiedlich zu beurteilen. Auch bei Jahrzehnte zurückliegender vollst?ndiger und dokumentierter Grundimmunisierung reicht eine einmalige Boosterimpfung aus, um einen vollst?ndigen Impfschutz zu induzieren. Nicht so bei unbekannter, aus dem Ged?chtnis benannter, Impfanamnese. Hier ist eine Vervollst?ndigung der Grundimmunisierung zwingend erforderlich. Summary  In 1996, 1378 sera of persons of different age were examined for neutralizing diphtheria antitoxin levels by the cell culture test according to Miyamura to evaluate the diphtheria immunity situation among the population in Saxony (immunity register). In 203 persons in which revaccination was indicated, the booster capacity has been evaluated by the same method based on the documented basic immunization, the number of revaccinations and the time which had passed since the last vaccination. Recording of the respective personal data, serum production and vaccination were performed by the public health departments according to a specific programme. The overallimmunity situation among the population in Saxony which is presumably representative of all new Federal L?nder was rated as still sufficient due to compulsory vaccination that had been performed between 1961 and 1990: 70% showed sufficient, 17.7% a relative and only 12.3% no protection. The immunity situation in persons above 40 years of age was unsatisfactory. Whether there is a booster capacity will depend on the documented basic immunization. A single booster vaccination is sufficient in order to induce complete protection, even if the complete and documented basic immunization took place decades ago. This is not the case when the vaccination history has been recalled by vacciness from their personal memory. In this case, completion of basic immunization is an absolute necessity.