BRCA1-regulated RRM2 expression protects glioblastoma cells from endogenous replication stress and promotes tumorigenicity.

Oncogene-evoked replication stress (RS) fuels genomic instability in diverse cancer types. Here we report that BRCA1, traditionally regarded a tumour suppressor, plays an unexpected tumour-promoting role in glioblastoma (GBM), safeguarding a protective response to supraphysiological RS levels. Higher BRCA1 positivity is associated with shorter survival of glioma patients and the abrogation of BRCA1 function in GBM enhances RS, DNA damage (DD) accumulation and impairs tumour growth.

Tumors overexpressing RNF168 show altered DNA repair and responses to genotoxic treatments, genomic instability and resistance to proteotoxic stress.

Chromatin DNA damage response (DDR) is orchestrated by the E3 ubiquitin ligase ring finger protein 168 (RNF168), resulting in ubiquitin-dependent recruitment of DDR factors and tumor suppressors breast cancer 1 (BRCA1) and p53 binding protein 1 (53BP1). This ubiquitin signaling regulates pathway choice for repair of DNA double-strand breaks (DSB), toxic lesions whose frequency increases during tumorigenesis. Recruitment of 53BP1 curbs DNA end resection, thereby limiting homologous recombination (HR) and directing DSB repair toward error-prone non-homologous end joining (NHEJ).

Role of DNA Repair Factor Xeroderma Pigmentosum Protein Group C in Response to Replication Stress As Revealed by DNA Fragile Site Affinity Chromatography and Quantitative Proteomics.

Replication stress (RS) fuels genomic instability and cancer development and may contribute to aging, raising the need to identify factors involved in cellular responses to such stress. Here, we present a strategy for identification of factors affecting the maintenance of common fragile sites (CFSs), which are genomic loci that are particularly sensitive to RS and suffer from increased breakage and rearrangements in tumors. A DNA probe designed to match the high flexibility island sequence typical for the commonly expressed CFS (FRA16D) was used as specific DNA affinity bait.

Two-Step Mechanism of Cellular Uptake of Cationic Gold Nanoparticles Modified by (16-Mercaptohexadecyl)trimethylammonium Bromide.

Cationic colloidal gold nanorods (GNRs) have a great potential as a theranostic tool for diverse medical applications. GNRs' properties such as cellular internalization and stability are determined by physicochemical characteristics of their surface coating. GNRs modified by (16-mercaptohexadecyl)trimethylammonium bromide (MTAB), GNRs, show excellent cellular uptake.

Sensitizing ovarian cancer cells to chemotherapy by interfering with pathways that are involved in the formation of cancer stem cells.

Chemotherapy often fails to eradicate cancer stem cells (CSCs) that drive cancer recurrence. In fact, the treated tumors often contain a higher frequency of chemo-resistant CSCs. It is thought that CSC formation is supported by exposure of cancer cells to sub-cytotoxic chemotherapy doses as a result of poor drug penetration in epithelial tumors.

DNA replication stress mediates APOBEC3 family mutagenesis in breast cancer.

Background: The APOBEC3 family of cytidine deaminases mutate the cancer genome in a range of cancer types. Although many studies have documented the downstream effects of APOBEC3 activity through next-generation sequencing, less is known about their upstream regulation. In this study, we sought to identify a molecular basis for APOBEC3 expression and activation.

FANCM c.5101C>T mutation associates with breast cancer survival and treatment outcome.

Breast cancer (BC) is a heterogeneous disease, and different tumor characteristics and genetic variation may affect the clinical outcome. The FANCM c.5101C > T nonsense mutation in the Finnish population associates with increased risk of breast cancer, especially for triple-negative breast cancer patients.

A genome-wide screening uncovers the role of CCAR2 as an antagonist of DNA end resection.

There are two major and alternative pathways to repair DNA double-strand breaks: non-homologous end-joining and homologous recombination. Here we identify and characterize novel factors involved in choosing between these pathways; in this study we took advantage of the SeeSaw Reporter, in which the repair of double-strand breaks by homology-independent or -dependent mechanisms is distinguished by the accumulation of green or red fluorescence, respectively. Using a genome-wide human esiRNA (endoribonuclease-prepared siRNA) library, we isolate genes that control the recombination/end-joining ratio.

RECQ5 helicase promotes resolution of conflicts between replication and transcription in human cells.

Collisions between replication and transcription machineries represent a significant source of genomic instability. RECQ5 DNA helicase binds to RNA-polymerase (RNAP) II during transcription elongation and suppresses transcription-associated genomic instability. Here, we show that RECQ5 also associates with RNAPI and enforces the stability of ribosomal DNA arrays.

Tumor growth accelerated by chemotherapy-induced senescent cells is suppressed by treatment with IL-12 producing cellular vaccines.

Standard-of-care chemo- or radio-therapy can induce, besides tumor cell death, also tumor cell senescence. While senescence is considered to be a principal barrier against tumorigenesis, senescent cells can survive in the organism for protracted periods of time and they can promote tumor development. Based on this emerging concept, we hypothesized that elimination of such potentially cancer-promoting senescent cells could offer a therapeutic benefit.

Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing.

The cyclin-dependent kinase inhibitor p21(WAF1/CIP1) (p21) is a cell-cycle checkpoint effector and inducer of senescence, regulated by p53. Yet, evidence suggests that p21 could also be oncogenic, through a mechanism that has so far remained obscure. We report that a subset of atypical cancerous cells strongly expressing p21 showed proliferation features.

Standardized reporting of adverse events after microvascular decompression of cranial nerves; a population-based single-institution consecutive series.

Objective: To investigate frequencies of adverse events occurring within 30 days after microvascular decompression (MVD) surgery using a standardized report form of adverse events.

Methods: We conducted a retrospective review of 98 adult patients (≥16 years) treated with MVD between 1 January 1994 and 1 June 2013. Adverse events occurring within 30 days were classified according to the Landriel Ibanez classification for neurosurgical complications: grade I represents any non-life threatening complication treated without invasive procedures; grade II is complications requiring invasive management; grade III is life-threatening adverse events requiring treatment in an intensive care unit (ICU); grade IV is death as a result of complications.

Hyperbaric oxygen therapy in spontaneous brain abscess patients: a population-based comparative cohort study.

Background: There is a need to improve outcome in patients with brain abscesses and hyperbaric oxygen therapy (HBOT) is a promising treatment modality. The objective of this study was to evaluate HBOT in the treatment of intracranial abscesses.

Method: This population-based, comparative cohort study included 40 consecutive adult patients with spontaneous brain abscess treated surgically between January 2003 and May 2014 at our institution.

Interferon gamma/NADPH oxidase defense system in immunity and cancer.

As a part of cellular pathogen defense, IFNγ triggers induction of NADPH oxidase NOX2, which produces superoxide into phagosomes of immune cells. Recent data show that a similar mechanism can also operate in IFNγ-mediated anticancer control. IFNγ is capable of inducing expression of constitutively active NADPH oxidase NOX4 in tumor cells leading to generation of reactive oxygen species (ROS) damaging DNA, activation of DNA damage response and cell cycle arrest/premature cellular senescence.

Neuron-Specific Enolase Is Correlated to Compromised Cerebral Metabolism in Patients Suffering from Acute Bacterial Meningitis; An Observational Cohort Study.

Introduction: Patients suffering from acute bacterial meningitis (ABM) with a decreased level of consciousness have been shown to have an improved clinical outcome if treated with an intracranial pressure (ICP) guided therapy. By using intracranial microdialysis (MD) to monitor cerebral metabolism in combination with serum samples of biomarkers indicating brain tissue injury, S100B and Neuron Specific Enolase (NSE), additional information might be provided. The aim of this study was to evaluate biomarkers in serum and MD parameters in patients with ABM.

DNA damage signalling barrier, oxidative stress and treatment-relevant DNA repair factor alterations during progression of human prostate cancer.

The DNA damage checkpoints provide an anti-cancer barrier in diverse tumour types, however this concept has remained unexplored in prostate cancer (CaP). Furthermore, targeting DNA repair defects by PARP1 inhibitors (PARPi) as a cancer treatment strategy is emerging yet requires suitable predictive biomarkers. To address these issues, we performed immunohistochemical analysis of multiple markers of DNA damage signalling, oxidative stress, DNA repair and cell cycle control pathways during progression of human prostate disease from benign hyperplasia, through intraepithelial neoplasia to CaP, complemented by genetic analyses of TMPRSS2-ERG rearrangement and NQO1, an anti-oxidant factor and p53 protector.

Adaptive hypofractionated gamma knife radiosurgery for a large brainstem metastasis.

Background: To demonstrate how adaptive hypofractionated radiosurgery by gamma knife (GK) can be successfully utilized to treat a large brainstem metastasis - a novel approach to a challenging clinical situation.

Case Description: A 42-year-old woman, diagnosed with metastatic nonsmall cell lung cancer in July 2011, initially treated with chemotherapy and tyrosine kinase inhibitors, developed multiple brain metastases March 2013, with subsequent whole brain radiotherapy, after which a magnetic resonance imaging (MRI) showed a significant volume regression of all brain metastases. A follow-up MRI in October 2013 revealed a growing brainstem lesion of 26 mm.

Intra-arterial nimodipine for cerebral vasospasm after subarachnoid haemorrhage: Influence on clinical course and predictors of clinical outcome.

Intra-arterial nimodipine (IAN) has shown a promising effect on cerebral vasospasm (CV) after aneurysmal subarachnoid haemorrhage. At our institution, Rigshospitalet, IAN treatment has been used since 2009, but the short- and long-term clinical efficacy of IAN has not yet been assessed. The purpose was to evaluate the efficacy and clinical outcome of IAN treatment of symptomatic CV, and to assess the predictors of clinical outcome.

Cellular microenvironment controls the nuclear architecture of breast epithelia through β1-integrin.

Defects in nuclear architecture occur in a variety of diseases, however the fundamental mechanisms that control the internal structure of nuclei are poorly defined. Here we reveal that the cellular microenvironment has a profound influence on the global internal organization of nuclei in breast epithelia. A 3D microenvironment induces a prolonged but reversible form of cell cycle arrest that features many of the classical markers of cell senescence.

TOPBP1 regulates RAD51 phosphorylation and chromatin loading and determines PARP inhibitor sensitivity.

Topoisomerase IIβ-binding protein 1 (TOPBP1) participates in DNA replication and DNA damage response; however, its role in DNA repair and relevance for human cancer remain unclear. Here, through an unbiased small interfering RNA screen, we identified and validated TOPBP1 as a novel determinant whose loss sensitized human cells to olaparib, an inhibitor of poly(ADP-ribose) polymerase. We show that TOPBP1 acts in homologous recombination (HR) repair, impacts olaparib response, and exhibits aberrant patterns in subsets of human ovarian carcinomas.

Cells and Stripes: A novel quantitative photo-manipulation technique.

Laser micro-irradiation is a technology widely used in the DNA damage response, checkpoint signaling, chromatin remodeling and related research fields, to assess chromatin modifications and recruitment of diverse DNA damage sensors, mediators and repair proteins to sites of DNA lesions. While this approach has aided numerous discoveries related to cell biology, maintenance of genome integrity, aging and cancer, it has so far been limited by a tedious manual definition of laser-irradiated subcellular regions, with the ensuing restriction to only a small number of cells treated and analyzed in a single experiment. Here, we present an improved and versatile alternative to the micro-irradiation approach: Quantitative analysis of photo-manipulated samples using innovative settings of standard laser-scanning microscopes.

Venous Thromboembolism Prophylaxis in Meningioma Surgery: A Population-Based Comparative Effectiveness Study of Routine Mechanical Prophylaxis with or without Preoperative Low-Molecular-Weight Heparin.

Objectives: Venous thromboembolism (VTE) is a serious complication after intracranial meningioma surgery. To what extent systemic prophylaxis with pharmacotherapy is beneficial with respect to VTE risk, or associated with increased risk of bleeding and postoperative hemorrhage, remains debated. The current study aimed to clarify the risk/benefit ratio of prophylactic pharmacotherapy initiated the evening before craniotomy for meningioma.

Valved or valveless ventriculoperitoneal shunting in the treatment of post-haemorrhagic hydrocephalus: a population-based consecutive cohort study.

Background: Implant infection and obstruction are major complications for ventriculoperitoneal shunts in patients with post-haemorrhagic hydrocephalus. In an effort to (1) reduce the incidence of these complications, (2) reduce the rate of shunt failure and (3) shorten the duration of neurosurgical hospitalisation, we have implemented valveless ventriculoperitoneal shunts at our department for adult patients with post-haemorrhagic hydrocephalus and haemorrhagic cerebrospinal fluid at the time of shunt insertion.

Methods: All adult patients (>18 years old) treated for post-haemorrhagic hydrocephalus with ventriculoperitoneal shunting at our institution from 1 January 2008 to 31 December 2014 were included in this retrospective population-based consecutive cohort study.

p38- and MK2-dependent signalling promotes stress-induced centriolar satellite remodelling via 14-3-3-dependent sequestration of CEP131/AZI1.

Centriolar satellites (CS) are small granular structures that cluster in the vicinity of centrosomes. CS are highly susceptible to stress stimuli, triggering abrupt displacement of key CS factors. Here we discover a linear p38-MK2-14-3-3 signalling pathway that specifically targets CEP131 to trigger CS remodelling after cell stress.