Osteosarcomagenesis: Biology, Development, Metastasis, and Mechanisms of Pain

Osteosarcoma is the most common primary cancer of the bone and third most common cancer in children and adolescents with approximately 900 new cases annually in the United States. A major facet of osteosarcoma is its high level of genomic instability, in particular chromosomal instability, which is the result of increased or decreased chromosome number in a cell. Furthermore, pain is the most common symptomatic feature of osteosarcoma that lacks effective therapy. Pain in osteosarcoma is relatively more complicated than many other painful conditions requiring a more thorough understanding of its etiology, pathobiology, and neurobiology to allow the development of better therapies for reducing pain in osteosarcoma patients. Studies are underway to define the diverse modalities of presentation, growth, development, metastases, and nociception in osteosarcoma. New data from human studies in combination with data from studies incorporating transgenic mouse models of osteosarcoma are providing valuable insights into the mechanisms underlying the development of both the tumor and the tumor-induced pain. These new data will undoubtedly lead to improved prognoses, as well as the development of novel therapeutics that will significantly decrease bone cancer pain

The Role for Coagulation Markers in Mild Snakebite Envenomations

Introduction: The majority of patients seeking medical treatment for snakebites do not suffer from severe envenomation. However, no guidelines exist for ordering coagulation markers in patients with minimal or moderate envenomation, nor in those who do not receive antivenom. In this study, we sought to determine whether it was possible to limit the practice of ordering coagulation studies to those patients suffering severe envenomation, rattlesnake envenomation, or both.Methods: A retrospective chart review was performed on all cases of crotalid snakebite presenting to an adult emergency department (ED) from April 1998 to June 2006. Each chart was abstracted for patient’s age, gender, type of snake (if known), severity of envenomation at initial presentation, coagulation test results, whether antivenom was administered, and whether the patient was admitted.Results: Over an approximately 8-year period, 131 snakebite cases presented that met the inclusion criteria, of which 35 (26.7%) had some type of coagulation marker abnormality. Limiting coagulation testing to patients suffering severe envenomation or rattlesnake envenomation would have resulted in failure to identify 89% or 77%, respectively, of the 35 patients who were found to have at least 1 abnormal coagulation marker.Conclusion: Our study failed to identify a subset of patients that could be defined as low risk or for whom coagulation marker testing could be foregone. This study suggests that coagulation tests should be routinely performed on all patients presenting to the ED with complaints of envenomation by copperheads, moccasins, or rattlesnakes. Further clarification of when coagulation markers are indicated may require a prospective study that standardizes snake identification and the timing of coagulation marker testing. [West J Emerg Med. 2012;13(1):68–74.

Relative importance of βcyto- and γcyto-actin in primary mouse embryonic fibroblasts

The highly homologous β (βcyto) and γ (γcyto) cytoplasmic actins are hypothesized to carry out both redundant and unique essential functions, but studies using targeted gene knockout and siRNA-mediated transcript knockdown to examine βcyto- and γcyto-isoform--specific functions in various cell types have yielded conflicting data. Here we quantitatively characterized actin transcript and protein levels, as well as cellular phenotypes, in both gene- and transcript-targeted primary mouse embryonic fibroblasts. We found that the smooth muscle αsm-actin isoform was the dominantly expressed actin isoform in WT primary fibroblasts and was also the most dramatically up-regulated in primary βcyto- or β/γcyto-actin double-knockout fibroblasts. Gene targeting of βcyto-actin, but not γcyto-actin, led to greatly decreased cell proliferation, decreased levels of cellular ATP, and increased serum response factor signaling in primary fibroblasts, whereas immortalization induced by SV40 large T antigen supported fibroblast proliferation in the absence of βcyto-actin. Consistent with in vivo gene-targeting studies in mice, both gene- and transcript-targeting approaches demonstrate that the loss of βcyto-actin protein is more disruptive to primary fibroblast function than is the loss of γcyto-actin

Engineering a hyperactive TcBuster transposase for efficient gene delivery for cell therapy applications

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Engineering Genetic Predisposition in Human Neuroepithelial Stem Cells Recapitulates Medulloblastoma Tumorigenesis.

Human neural stem cell cultures provide progenitor cells that are potential cells of origin for brain cancers. However, the extent to which genetic predisposition to tumor formation can be faithfully captured in stem cell lines is uncertain. Here, we evaluated neuroepithelial stem (NES) cells, representative of cerebellar progenitors. We transduced NES cells with MYCN, observing medulloblastoma upon orthotopic implantation in mice. Significantly, transcriptomes and patterns of DNA methylation from xenograft tumors were globally more representative of human medulloblastoma compared to a MYCN-driven genetically engineered mouse model. Orthotopic transplantation of NES cells generated from Gorlin syndrome patients, who are predisposed to medulloblastoma due to germline-mutated PTCH1, also generated medulloblastoma. We engineered candidate cooperating mutations in Gorlin NES cells, with mutation of DDX3X or loss of GSE1 both accelerating tumorigenesis. These findings demonstrate that human NES cells provide a potent experimental resource for dissecting genetic causation in medulloblastoma

Application of geographic information systems and simulation modelling to dental public health: Where next?

Public health research in dentistry has used geographic information systems since the 1960s. Since then, the methods used in the field have matured, moving beyond simple spatial associations to the use of complex spatial statistics and, on occasions, simulation modelling. Many analyses are often descriptive in nature; however, and the use of more advanced spatial simulation methods within dental public health remains rare, despite the potential they offer the field. This review introduces a new approach to geographical analysis of oral health outcomes in neighbourhoods and small area geographies through two novel simulation methods-spatial microsimulation and agent-based modelling. Spatial microsimulation is a population synthesis technique, used to combine survey data with Census population totals to create representative individual-level population datasets, allowing for the use of individual-level data previously unavailable at small spatial scales. Agent-based models are computer simulations capable of capturing interactions and feedback mechanisms, both of which are key to understanding health outcomes. Due to these dynamic and interactive processes, the method has an advantage over traditional statistical techniques such as regression analysis, which often isolate elements from each other when testing for statistical significance. This article discusses the current state of spatial analysis within the dental public health field, before reviewing each of the methods, their applications, as well as their advantages and limitations. Directions and topics for future research are also discussed, before addressing the potential to combine the two methods in order to further utilize their advantages. Overall, this review highlights the promise these methods offer, not just for making methodological advances, but also for adding to our ability to test and better understand theoretical concepts and pathways