There is, I think, something ethereal about i —the square root of minus one. I remember first hearing about it at school. It seemed an odd beast at that time—an intruder hovering on the edge of reality.

Usually familiarity dulls this sense of the bizarre, but in the case of i it was the reverse: over the years the sense of its surreal nature intensified. It seemed that it was impossible to write mathematics that described the real world in …

I and i

The cancer stem cell (CSC) hypothesis suggests that neoplastic clones are maintained exclusively by a rare fraction of cells with stem cell properties. Although the existence of CSCs in human leukaemia is established, little evidence exists for CSCs in solid tumours, except for breast cancer. Recently, we prospectively isolated a CD133+ cell subpopulation from human brain tumours that exhibited stem cell properties in vitro. However, the true measures of CSCs are their capacity for self renewal and exact recapitulation of the original tumour. Here we report the development of a xenograft assay that identified human brain tumour initiating cells that initiate tumours in vivo. Only the CD133+ brain tumour fraction contains cells that are capable of tumour initiation in NOD-SCID (non-obese diabetic, severe combined immunodeficient) mouse brains. Injection of as few as 100 CD133+ cells produced a tumour that could be serially transplanted and was a phenocopy of the patient's original tumour, whereas injection of 10(5) CD133- cells engrafted but did not cause a tumour. Thus, the identification of brain tumour initiating cells provides insights into human brain tumour pathogenesis, giving strong support for the CSC hypothesis as the basis for many solid tumours, and establishes a previously unidentified cellular target for more effective cancer therapies.

Identification of human brain tumour initiating cells

Most current research on human brain tumors is focused on the molecular and cellular analysis of the bulk tumor mass. However, there is overwhelming evidence in some malignancies that the tumor clone is heterogeneous with respect to proliferation and differentiation. In human leukemia, the tumor clone is organized as a hierarchy that originates from rare leukemic stem cells that possess extensive proliferative and self-renewal potential, and are responsible for maintaining the tumor clone. We report here the identification and purification of a cancer stem cell from human brain tumors of different phenotypes that possesses a marked capacity for proliferation, self-renewal, and differentiation. The increased self-renewal capacity of the brain tumor stem cell (BTSC) was highest from the most aggressive clinical samples of medulloblastoma compared with low-grade gliomas. The BTSC was exclusively isolated with the cell fraction expressing the neural stem cell surface marker CD133. These CD133+ cells could differentiate in culture into tumor cells that phenotypically resembled the tumor from the patient. The identification of a BTSC provides a powerful tool to investigate the tumorigenic process in the central nervous system and to develop therapies targeted to the BTSC.

https://cancerres.aacrjournals.org/content/canres/63/18/5821.full.pdf

Identification of a Cancer Stem Cell in Human Brain Tumors

The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

Integrative analysis of 111 reference human epigenomes

Approximately 5% of patients with malignant gliomas have a family history of gliomas. Some of these familial cases are associated with rare genetic syndromes, such as neurofibromatosis types 1 and 2, the Li−Fraumeni syndrome (germ-line p53 mutations associated with an increased risk of several cancers), and Turcot’s syndrome (intestinal polyposis and brain tumors). 10 However, most familial cases have

Malignant Gliomas in Adults

Platelet-derived Growth Factor and Its Receptor Expression in Human Oligodendrogliomas

A complex series of molecular signaling events are responsible for cell division. Early in the cell cycle, cues determine whether a cell will initiate a round of replication or withdraw from cell division and enter a state of quiescence. Passage through the restriction point (RP), designated the “point of no return”, marks cellular commitment to a new round of division. Genetic mutations affecting molecules that control proliferation predispose to tumorigenesis. Many of the identified mutations associated with cancer cells give rise to molecules that are no longer able to appropriately regulate the mammalian cell cycle and the end result is neoplasia. Here, we review the critical elements that enable cell cycle progression as well as the positive and negative regulators that facilitate the process. In addition, the development and implementation of therapeutic modalities that exploit cell cycle inhibition are examined.

Regulation of the Cell Cycle and Interventional Developmental Therapeutics

Epileptogenic modulation index and synchronization in hypsarrhythmia of West syndrome secondary to perinatal arterial ischemic stroke

Identification of the epileptogenic zone is a critical determinant of seizure control outcomes following surgical resection in medically refractory seizures. There has been increasing recognition of the contributive value of Magnetoencephalography (MEG) studies in the diagnostic evaluation of epilepsy. Biomagnetic signals recorded by MEG studies in combination with source modeling techniques can yield diagnostic information regarding the underlying epileptogenic zone. MEG evaluation is particularly useful in evaluation of non lesional neocortical epilepsy. In these cases, MEG spike sources can guide presurgical and perioperative invasive monitoring. The incorporation of MEG-based diagnostic information into the surgical evaluation and management plan has consistently been shown to be associated with improved seizure control outcomes.

The role of MEG in pre-surgical evaluation of epilepsy: current use and future directions

Postsurgical deep brain venous thrombosis has not been well described in children before. When approaching thalamic or intraventricular lesions, extra care should be taken to prevent injury to the internal cerebral veins (ICVs) and the vein of Galen. However, even when they are well preserved during surgery, postoperative hemodynamic changes, mainly in the first 24 h, or surgical manipulation can cause thrombosis of these veins. We report 2 children with unilateral postoperative ICV thrombosis; in 1 of the patients the vein of Galen was also thrombosed. Although both patients had altered sensorium initially, no anticoagulation therapy was given, and they both recovered well. When approaching thalamic or intraventricular lesions, extra care should be taken to prevent injury to the ICV and the vein of Galen. The surgeon should respect the deep brain venous system when approaching midline structures. Both the neurosurgeon and the neuroradiologist should be aware of this possible complication in order to make a prompt diagnosis and to offer proper treatment if needed.

James T. Rutka

Papers

Platelet-derived Growth Factor and Its Receptor Expression in Human Oligodendrogliomas

Regulation of the Cell Cycle and Interventional Developmental Therapeutics

Epileptogenic modulation index and synchronization in hypsarrhythmia of West syndrome secondary to perinatal arterial ischemic stroke

The role of MEG in pre-surgical evaluation of epilepsy: current use and future directions

Unilateral Postoperative Deep Cerebral Venous Thrombosis with Complete Recovery: A Report of 2 Cases.