An infectious aetiology for childhood brain tumours? Evidence from space–time clustering and seasonality analyses

To investigate whether infections or other environmental exposures may be involved in the aetiology of childhood central nervous system tumours, we have analysed for space–time clustering and seasonality using population-based data from the North West of England for the period 1954 to 1998. Knox tests for space–time interactions between cases were applied with fixed thresholds of close in space, <5 km, and close in time, <1 year apart. Addresses at birth and diagnosis were used. Tests were repeated replacing geographical distance with distance to the Nth nearest neighbour. N was chosen such that the mean distance was 5 km. Data were also examined by a second order procedure based on K-functions. Tests for heterogeneity and Edwards' test for sinusoidal variation were applied to examine changes of incidence with month of birth or diagnosis. There was strong evidence of space–time clustering, particularly involving cases of astrocytoma and ependymoma. Analyses of seasonal variation showed excesses of cases born in the late Autumn or Winter. Results are consistent with a role for infections in a proportion of cases from these diagnostic groups. Further studies are needed to identify putative infectious agents

Chronic Viral Infection and Primary Central Nervous System Malignancy

Primary central nervous system (CNS) tumors cause significant morbidity and mortality in both adults and children. While some of the genetic and molecular mechanisms of neuro-oncogenesis are known, much less is known about possible epigenetic contributions to disease pathophysiology. Over the last several decades, chronic viral infections have been associated with a number of human malignancies. In primary CNS malignancies, two families of viruses, namely polyomavirus and herpesvirus, have been detected with varied frequencies in a number of pediatric and adult histological tumor subtypes. However, establishing a link between chronic viral infection and primary CNS malignancy has been an area of considerable controversy, due in part to variations in detection frequencies and methodologies used among researchers. Since a latent viral neurotropism can be seen with a variety of viruses and a widespread seropositivity exists among the population, it has been difficult to establish an association between viral infection and CNS malignancy based on epidemiology alone. While direct evidence of a role of viruses in neuro-oncogenesis in humans is lacking, a more plausible hypothesis of neuro-oncomodulation has been proposed. The overall goals of this review are to summarize the many human investigations that have studied viral infection in primary CNS tumors, discuss potential neuro-oncomodulatory mechanisms of viral-associated CNS disease and propose future research directions to establish a more firm association between chronic viral infections and primary CNS malignancies

Impaired CK1 Delta Activity Attenuates SV40-Induced Cellular Transformation In Vitro and Mouse Mammary Carcinogenesis In Vivo

Simian virus 40 (SV40) is a powerful tool to study cellular transformation in vitro, as well as tumor development and progression in vivo. Various cellular kinases, among them members of the CK1 family, play an important role in modulating the transforming activity of SV40, including the transforming activity of T-Ag, the major transforming protein of SV40, itself. Here we characterized the effects of mutant CK1δ variants with impaired kinase activity on SV40-induced cell transformation in vitro, and on SV40-induced mammary carcinogenesis in vivo in a transgenic/bi-transgenic mouse model. CK1δ mutants exhibited a reduced kinase activity compared to wtCK1δ in in vitro kinase assays. Molecular modeling studies suggested that mutation N172D, located within the substrate binding region, is mainly responsible for impaired mutCK1δ activity. When stably over-expressed in maximal transformed SV-52 cells, CK1δ mutants induced reversion to a minimal transformed phenotype by dominant-negative interference with endogenous wtCK1δ. To characterize the effects of CK1δ on SV40-induced mammary carcinogenesis, we generated transgenic mice expressing mutant CK1δ under the control of the whey acidic protein (WAP) gene promoter, and crossed them with SV40 transgenic WAP-T-antigen (WAP-T) mice. Both WAP-T mice as well as WAP-mutCK1δ/WAP-T bi-transgenic mice developed breast cancer. However, tumor incidence was lower and life span was significantly longer in WAP-mutCK1δ/WAP-T bi-transgenic animals. The reduced CK1δ activity did not affect early lesion formation during tumorigenesis, suggesting that impaired CK1δ activity reduces the probability for outgrowth of in situ carcinomas to invasive carcinomas. The different tumorigenic potential of SV40 in WAP-T and WAP-mutCK1δ/WAP-T tumors was also reflected by a significantly different expression of various genes known to be involved in tumor progression, specifically of those involved in wnt-signaling and DNA repair. Our data show that inactivating mutations in CK1δ impair SV40-induced cellular transformation in vitro and mouse mammary carcinogenesis in vivo

Adenovirus type 12 early region 1A proteins repress class I HLA expression in transformed human cells.

The adenovirus type 12 (Ad12) early region 1A (E1A) gene is thought to play a major role in repressing class I major histocompatibility complex expression in transformed rodent cells. However, since transformation by adenovirus requires both E1A and E1B genes, it has not been demonstrated whether the Ad12 E1A gene acts alone or synergistically with the E1B gene to accomplish this effect. Moreover, it is not known whether the repression of class I antigen synthesis by Ad12-transforming gene products occurs only in rodent cells. We show that the Ad12 E1A gene, in the absence of the E1B gene, is capable of greatly reducing the levels of class I HLA antigens and mRNAs in primary human cells transformed by the E1A gene of Ad12 and the large tumor antigen (T-antigen) gene of BK virus; control cells transformed by BK virus T-antigen gene alone or the highly related simian virus 40 T-antigen gene showed no apparent alteration in class I HLA expression. Human recombinant interferon gamma was able to restore synthesis of class I HLA antigens in transformed cells that produced Ad12 E1A proteins, indicating that these cells were not deficient for class I genes. These results strongly indicate that the Ad12 E1A proteins modulate class I gene expression by similar mechanisms in both transformed rodent and human cells

Substantial overview on mesenchymal stem cell biological and physical properties as an opportunity in translational medicine

Mesenchymal stem cells (MSC) have piqued worldwide interest for their extensive potential to treat a large array of clinical indications, their unique and controversial immunogenic and immune modulatory properties allowing ample discussions and debates for their possible applications. Emerging data demonstrating that the interaction of biomaterials and physical cues with MSC can guide their differentiation into specific cell lineages also provide new interesting insights for further MSC manipulation in different clinical applications. Moreover, recent discoveries of some regulatory molecules and signaling pathways in MSC niche that may regulate cell fate to distinct lineage herald breakthroughs in regenerative medicine. Although the advancement and success in the MSC field had led to an enormous increase in the amount of ongoing clinical trials, we still lack defined clinical therapeutic protocols. This review will explore the exciting opportunities offered by human and animal MSC, describing relevant biological properties of these cells in the light of the novel emerging evidence mentioned above while addressing the limitations and challenges MSC are still facing

Does capacitively coupled electric fields stimulation improve clinical outcomes after instrumented spinal fusion? A multicentered randomized, prospective, double-blind, placebo-controlled trial

Background: Lumbar spinal fusion (LSF) is used to treat lumbar degenerative disorders. Methods to improve the functional recovery of patients undergoing LSF is one of the main goals in daily clinical practice. The objective of this study is to assess whether biophysical stimulation with capacitively coupled electric fields (CCEF) can be used as adjuvant therapy to enhance clinical outcome in LSF-treated patients. Methods: Forty-two patients undergoing LSF were assessed and randomly allocated to either the active or to the placebo group. Follow-up visits were performed at 1, 3, 6, and 12 months after surgery; long-term follow-up was performed at year 10. Visual analogue scale (VAS), the Oswestry Disability Index (ODI), and the 36-item Short Form Health Survey (SF-36) questionnaire were recorded. Results: This study demonstrates a significant improvement in CCEF-treated patients at 6 and 12 months’ followup for SF-36, and at 12 months’ follow-up for ODI values. Based on SF-36 and ODI scores, we reported a significantly higher percentage of successful treatments at 12 months in the active compared with the placebo group. Moreover, in a subset of patients at 10 years’ follow-up, a significant difference was reported in VAS and ODI scores between groups. Conclusions: The results demonstrate that 3 months of CCEF treatment immediately after surgery is effective in reducing ODI and improving SF-36 score, and that these benefits can be maintained up to 12 months. In a subset of patients, these positive outcomes are retained up to 10 years