Effect of teleradiology upon pattern of transfer of head injured patients from a rural general hospital to a neurosurgical referral centre.

Objective: To assess the effect of teleradiology upon the need for transfer of head injured victims requiring hospitalisation but referred initially to a rural level 2 trauma centre without neurosurgical capacity.

Methods: Head injured patients requiring hospitalisation, admitted to a rural level 2 trauma centre between August 2003 and August 2005, were identified. A digitalised copy of the computed tomographic (CT) scan was transferred to the neurosurgical referral centre via teleradiology and was available for review by the neurosurgeon on-call, who then, together with the trauma surgeon in the rural level 2 trauma centre, decided whether to transfer the patient to the neurosurgical referral centre.

Global and local architecture of the mammalian microRNA-transcription factor regulatory network.

microRNAs (miRs) are small RNAs that regulate gene expression at the posttranscriptional level. It is anticipated that, in combination with transcription factors (TFs), they span a regulatory network that controls thousands of mammalian genes. Here we set out to uncover local and global architectural features of the mammalian miR regulatory network.

The Nedd4-binding partner 1 (N4BP1) protein is an inhibitor of the E3 ligase Itch.

Nedd4-binding partner-1 (N4BP1) has been identified as a protein interactor and a substrate of the homologous to E6AP C terminus (HECT) domain-containing E3 ubiquitin-protein ligase (E3), Nedd4. Here, we describe a previously unrecognized functional interaction between N4BP1 and Itch, a Nedd4 structurally related E3, which contains four WW domains, conferring substrate-binding activity. We show that N4BP1 association with the second WW domain (WW2) of Itch interferes with E3 binding to its substrates.

Transcriptional activation of miR-34a contributes to p53-mediated apoptosis.

p53 is a potent tumor suppressor, whose biological effects are largely due to its function as a transcriptional regulator. Here we report that, in addition to regulating the expression of hundreds of protein-coding genes, p53 also modulates the levels of microRNAs (miRNAs). Specifically, p53 can induce expression of microRNA-34a (miR-34a) in cultured cells as well as in irradiated mice, by binding to a perfect p53 binding site located within the gene that gives rise to miR-34a.

The autophagic inducer smARF interacts with and is stabilized by the mitochondrial p32 protein.

The alternative reading frame (ARF) mRNA encodes two pro-death proteins, the nucleolar p19ARF and a shorter mitochondrial isoform, named smARF (hsmARF in human). While p19ARF can inhibit cell growth by causing cell cycle arrest or type I apoptotic cell death, smARF is able to induce type II autophagic cell death. Inappropriate proliferative signals generated by proto-oncogenes, such as c-Myc and E2F1, can elevate both p19ARF and smARF proteins.

Significance of a Level-2, "selective, secondary evacuation" hospital during a peripheral town terrorist attack.

Introduction: Mass-casualty incidents (MCIs) can occur outside of major metropolitan areas. In such circumstances, the nearest hospital seldom is a Level-1 Trauma Center. Moreover, emergency medical services (EMS) capabilities in such areas tend to be limited, which may compromise prehospital care and evacuation speed.

Transcription regulation by mutant p53.

In addition to the loss of wild-type p53 activity, a high percentage of tumor cells accumulate mutant p53 protein isoforms. Whereas the hallmark of the wild-type p53 is its tumor suppressor activities, tumor-associated mutant p53 proteins acquire novel functions enabling them to promote a large spectrum of cancer phenotypes. During the last years, it became clear that tumor-associated mutant p53 proteins are not only distinct from the wild-type p53, but they also represent a heterogeneous population of proteins with a variety of structure-function features.

Mdm2: p53's lifesaver?

In a recent issue of Molecular Cell, Taira et al. (2007) and Rinaldo et al. (2007) provide insight into the involvement of the DYRK2 kinase and a surprising role of MDM2 in regulation of DNA damage-induced apoptosis via p53 phosphorylation.

Mutant p53 enhances nuclear factor kappaB activation by tumor necrosis factor alpha in cancer cells.

Mutations in the p53 tumor suppressor are very frequent in human cancer. Often, such mutations lead to the constitutive overproduction of mutant p53 proteins, which may exert a cancer-promoting gain of function. We now report that cancer-associated mutant p53 can augment the induction of nuclear factor kappaB (NFkappaB) transcriptional activity in response to the cytokine tumor necrosis factor alpha (TNFalpha).

The sunny side of p53.

Skin, the largest organ of our body, is often plagued by cancer because of exposure to ultraviolet radiation from the sun. A report by Cui et al. (2007) in this issue of Cell explains how the tumor suppressor p53 protects the skin by stimulating the suntan response.

Identification of immune-relevant genes in histoincompatible rejecting colonies of the tunicate Botryllus schlosseri.

The colonial ascidian Botryllus schlosseri manifests a unique allorecognition system that is controlled by a single histocompatibility haplotype, the Fu/HC locus. When two allogeneic incompatible colonies come into direct contact, they develop inflammatory-like rejection lesions, called points of rejection (POR). While screening for differentially expressed genes during POR formation, we developed and analyzed a cDNA library of expressed sequence tags (ESTs) with 1693 unique ESTs that were clustered and assembled into 217 contigs and 1476 singlets.

p53 Attenuates cancer cell migration and invasion through repression of SDF-1/CXCL12 expression in stromal fibroblasts.

The p53 tumor suppressor acts as a major barrier against cancer. To a large extent, this is due to its ability to maintain genome stability and to eliminate cancer cells from the replicative pool through cell-autonomous mechanisms. However, in addition to its well-documented functions within the malignant cancer cell, p53 can also exert non-cell-autonomous effects that contribute to tumor suppression.

A positive feedback loop between the p53 and Lats2 tumor suppressors prevents tetraploidization.

Damage to the mitotic spindle and centrosome dysfunction can lead to cancer. To prevent this, cells trigger a succession of checkpoint responses, where an initial mitotic delay is followed by slippage without cytokinesis, spawning tetraploid G1 cells that undergo a p53-dependent G1/S arrest. We describe the importance of Lats2 (Large Tumor Suppressor 2) in this checkpoint response.

Regulation of AIF expression by p53.

The tumor suppressor p53 plays a pivotal role in suppressing tumorigenesis by inducing genomic stability, cell cycle arrest or apoptosis. AIF is a mitochondrial protein, which, upon translocation to the nucleus, can participate in apoptosis, primarily in a caspase-independent contexts. We now report that AIF gene expression is subject to positive transcriptional regulation by p53.

A short mitochondrial form of p19ARF induces autophagy and caspase-independent cell death.

The tumor suppressor functions of p19(ARF) have been attributed to its ability to induce cell cycle arrest or apoptosis by activating p53 and regulating ribosome biogenesis. Here we describe another cellular function of p19(ARF), involving a short isoform (smARF, short mitochondrial ARF) that localizes to a Proteinase K-resistant compartment of the mitochondria. smARF is a product of internal initiation of translation at Met45, which lacks the nucleolar functional domains.

p53 and p21 regulate error-prone DNA repair to yield a lower mutation load.

Regulation of mutation rates is critical for maintaining genome stability and controlling cancer risk. A special challenge to this regulation is the presence of multiple mutagenic DNA polymerases in mammals. These polymerases function in translesion DNA synthesis (TLS), an error-prone DNA repair process that involves DNA synthesis across DNA lesions.

Developing and implementing a model for changing physicians' prescribing habits-- the role of clinical pharmacy in leading the change.

Background And Objective: Budgetary constraints led the Israeli Hillel Yaffe Medical Center management to implement policies for reducing expenditure while maintaining the quality of care. For this purpose, the pharmacy services management developed and implemented a three-tier intervention feedback model for changing physicians' prescribing habits, and achieving cost-effective changes in antibiotic utilization.

Methods: A prospective drug utilization evaluation was conducted to profile antibiotic utilization.

Precision of in-hospital triage in mass-casualty incidents after terror attacks.

Introduction: Proper management of mass-casualty incidents (MCIs) relies on triage as a critical component of the disaster plan.

Objective: [corrected] The objective of this study was to assess the precision of triage in mass-casualty incidents.

Methods: The precision of decisions made by two experienced triage officers was examined in two large MCIs.

hTERT-immortalized prostate epithelial and stromal-derived cells: an authentic in vitro model for differentiation and carcinogenesis.

Prostate cancer is the most commonly diagnosed type of cancer in men, and there is no available cure for patients with advanced disease. In vitro model systems are urgently required to permit the study of human prostate cell differentiation and malignant transformation. Unfortunately, human prostate cells are particularly difficult to convert into continuously growing cultures.

BCL6 is regulated by p53 through a response element frequently disrupted in B-cell non-Hodgkin lymphoma.

The BCL6 transcriptional repressor mediates survival, proliferation, and differentiation blockade of B cells during the germinal-center reaction and is frequently misregulated in B-cell non-Hodgkin lymphoma (BNHL). The p53 tumor-suppressor gene is central to tumorigenesis. Microarray analysis identified BCL6 as a primary target of p53.

TAp73/Delta Np73 influences apoptotic response, chemosensitivity and prognosis in hepatocellular carcinoma.

We investigated the mechanisms by which TAp73 beta and dominant-negative p73 (Delta Np73) regulate apoptosis. TAp73 beta transactivated the CD95 gene via the p53-binding site in the first intron. In addition, TAp73 beta induced expression of proapoptotic Bcl-2 family members and led to apoptosis via the mitochondrial pathway.

Repression of the MSP/MST-1 gene contributes to the antiapoptotic gain of function of mutant p53.

Tumor-associated mutant forms of p53 can exert an antiapoptotic gain of function activity, which confers a selective advantage upon tumor cells harboring such mutations. We report that mutant p53 suppresses the expression of the MSP (MST-1/HGFL) gene, encoding the ligand of the receptor tyrosine kinase RON, implicated in a variety of cellular responses. Mutant p53 associates with the MSP gene promoter and represses its transcriptional activity, leading to a decrease in mRNA levels and a subsequent decrease in the levels of secreted MSP protein.

Life, death, and ubiquitin: taming the mule.

Ubiquitin-mediated protein degradation is an efficient way for the cell to get rid of unwanted proteins. A key player in this process is the E3 ubiquitin ligase. In this issue of Cell, and describe a new E3 ligase, ARF-BP1/Mule, which targets two very different substrates, p53 and Mcl-1, with completely different cellular outcomes.

TAp63alpha induces apoptosis by activating signaling via death receptors and mitochondria.

TP63, an important epithelial developmental gene, has significant homology to p53. Unlike p53, the expression of p63 is regulated by two different promoters resulting in proteins with opposite functions: the full-length transcriptionally active TAp63 and the dominant-negative DeltaNp63. We investigated the downstream mechanisms by which TAp63alpha elicits apoptosis.

The PI3K inhibitor LY294002 prevents p53 induction by DNA damage and attenuates chemotherapy-induced apoptosis.

The p53 tumor suppressor plays a key role in the natural protection against cancer. Activation of p53 by DNA-damaging agents can contribute to successful elimination of cancer cells via chemotherapy-induced apoptosis. The phosphatidylinositol-3 kinase (PI3K) pathway, triggered in normal cells upon exposure to growth factors, regulates a cascade of proliferation and survival signals.