Catalogue Search | MBRL
Are you sure you want to remove the book from the shelf?
{{itemTitle}}
1,098
result(s) for
"Schiff, David"
Sort by:
MicroRNA-608 and MicroRNA-34a Regulate Chordoma Malignancy by Targeting EGFR, Bcl-xL and MET
Chordomas are rare malignant tumors that originate from the notochord remnants and occur in the skull base, spine and sacrum. Due to a very limited understanding of the molecular pathogenesis of chordoma, there are no adjuvant and molecular therapies besides surgical resection and radiation therapy. microRNAs (miRNAs) are small noncoding regulatory RNA molecules with critical roles in cancer. The role of miRNAs in chordomas is mostly unknown. We uncover microRNA-608 (miR-608) and microRNA-34a (miR-34a) as novel tumor suppressive microRNAs that regulate malignancy in chordoma. We find that miR-608 and miR-34a expressions are downregulated in human chordoma cell lines and primary cells at least partially via alteration of their genes' copy numbers. We identify the commonly deregulated oncogenes EGFR and Bcl-xL as direct targets of miR-608 and the receptor tyrosine kinase MET as direct target of miR-34a. We show that EGFR and MET activations promote chordoma cell proliferation and invasion and that pharmacological inhibition of EGFR and MET inhibits chordoma cell proliferation and survival. We demonstrate that restoration of miR-608 and miR-34a inhibits cell proliferation and invasion and induces apoptosis in chordoma cells. We find that miR-34a inversely correlates with MET expression and miR-608 inversely correlates with EGFR expression in chordoma cells. These findings demonstrate for the first time that miR-608 and miR-34a regulate chordoma malignancy by regulating EGFR, MET and Bcl-xL.
Journal Article
Headway against Brain Tumors with Molecular Targeting of IDH-Mutant Gliomas
Approximately 2500 persons in the United States receive a diagnosis of isocitrate dehydrogenase (IDH)–mutated grade 2 glioma each year.
1
These patients tend to be young (median age, 40 years), and most have tumor-related epilepsy and grapple with a tumor that may affect cognition, employment, and other aspects of life. These tumors typically become refractory to treatment and are eventually fatal, belying their designation as “low-grade” gliomas. Both fractionated radiotherapy and alkylator-based chemotherapy help control these tumors but convey a substantial risk of permanent toxic effects. With radiation therapy, such effects include fatigue, alopecia, radiation necrosis, and particularly, cognitive dysfunction; chemotherapy . . .
Journal Article
Update on molecular findings, management and outcome in low-grade gliomas
Diagnosis of low-grade inflitrating gliomas—a class of brain tumors that includes diffuse astrocytoma, oligoastrocytoma and oligodendroglioma—currently relies largely on histological classification, although molecular discoveries are beginning to generate new paradigms for diagnosis and management. Bourne and Schiff highlight the molecular abnormalities that have been identified in low-grade gliomas, and discuss how factors such as chromosome 1p19q codeletion and
MGMT
promoter methylation status are facilitating stratification of patients in clinical trials.
Low-grade infiltrating gliomas in adults include diffuse astrocytoma, oligoastrocytoma and oligodendroglioma. The current gold standard diagnosis of these tumors relies on histological classification; however, emerging molecular abnormalities discovered in these tumors are playing an increasingly prominent part in the process of tumor diagnosis and, consequently, patient management. The frequency and clinical importance of tumor protein p53 (
TP53
) abnormalities, deletions involving chromosomes 1p and 19q,
O
6
-methylguanine-DNA methyltransferase (
MGMT
) promoter methylation status, abnormalities in the
PTEN
tumor suppressor gene and the
BRAF
oncogene, and isocitrate dehydrogenase (
IDH)
mutations have become better defined. Molecular markers have not, historically, had an important role in determining the course of treatment for patients with low-grade gliomas, but ongoing phase III clinical trials incorporate 1p deletion or 1p19q codeletion status—and future trials plan to incorporate
MGMT
promoter methylation status—as stratification factors. Future trials will need to incorporate
IDH
mutational status in addition to these factors. Ultimately, molecular marker assessment will, hopefully, improve the accuracy of tumor diagnosis and enhance the effectiveness of treatment to achieve improved patient outcomes.
Key Points
Isocitrate dehydrogenase (
IDH
) mutations seem to occur earlier than tumor protein p53 (
TP53
) mutations or deletions of chromosomes 1p and/or 19q among a subset of diffuse astrocytomas and oligodendroglial tumors
Tumors with 1p and/or 19q chromosomal deletions usually also have
IDH
mutations
1p19q codeletion and
IDH
mutation each have favorable prognostic value, with
IDH
-mutated, 1p19q-intact tumors having an outcome intermediate between 1p19q-codeleted tumors and tumors that lack either of these molecular markers
The independent prognostic importance of
O
6
-methylguanine-DNA methyltransferase (
MGMT
) promoter methylation remains to be determined
No molecular marker has yet been validated as predicting a favorable response to chemotherapy or radiation therapy
Journal Article
Response assessment after stereotactic body radiotherapy for spinal metastasis: a report from the SPIne response assessment in Neuro-Oncology (SPINO) group
The SPine response assessment In Neuro-Oncology (SPINO) group is a committee of the Response Assessment in Neuro-Oncology working group and comprises a panel of international experts in spine stereotactic body radiotherapy (SBRT). Here, we present the group's first report on the challenges in standardising imaging-based assessment of local control and pain for spinal metastases. We review current imaging modalities used in SBRT treatment planning and tumour assessment and review the criteria for pain and local control in registered clinical trials specific to spine SBRT. We summarise the results of an international survey of the panel to establish the range of current practices in assessing tumour response to spine SBRT. The ultimate goal of the SPINO group is to report consensus criteria for tumour imaging, clinical assessment, and symptom-based response criteria to help standardise future clinical trials.
Journal Article
Clinical trial design for systemic agents in patients with brain metastases from solid tumours: a guideline by the Response Assessment in Neuro-Oncology Brain Metastases working group
Patients with active CNS disease are often excluded from clinical trials, and data regarding the CNS efficacy of systemic agents are usually obtained late in the drug development process or not at all. In this guideline from the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group, we provide detailed recommendations on when patients with brain metastases from solid tumours should be included or excluded in clinical trials of systemic agents. We also discuss the limitations of retrospective studies in determining the CNS efficacy of systemic drugs. Inclusion of patients with brain metastases early on in the clinical development of a drug or a regimen is needed to generate appropriate CNS efficacy or non-efficacy signals. We consider how to optimally incorporate or exclude such patients in systemic therapy trials depending on the likelihood of CNS activity of the agent by considering three scenarios: drugs that are considered very unlikely to have CNS antitumour activity or efficacy; drugs that are considered very likely to have CNS activity or efficacy; and drugs with minimal baseline information on CNS activity or efficacy. We also address trial design issues unique to patients with brain metastases, including the selection of appropriate CNS endpoints in systemic therapy trials.
Journal Article
Treatment Considerations for MGMT-Unmethylated Glioblastoma
Prognosis for patients with glioblastoma continues to be limited, despite an aggressive, multimodal treatment including alkylating chemotherapy. Temozolomide, the most widely used alkylating agent in glioblastoma, is cytotoxic to cells by inducing DNA damage but can be rapidly repaired by the protein
O
6
-methylguanine DNA methyltransferase (MGMT). In a subset of glioblastomas, the
MGMT
promoter is methylated, impairing the repair mechanism and conferring chemosensitivity. However, MGMT is overexpressed in 60 % of glioblastomas providing an inherent resistance to alkylating agents and challenging the role of temozolomide in this population. This article reviews the data establishing
MGMT
promoter methylation as a prognostic factor in glioblastoma and its potential role as a predictor of temozolomide response. It focuses on results from recent studies in newly diagnosed glioblastoma, and the role of temozolomide in
MGMT
-unmethylated patients. We then turn the discussion to alternatives to temozolomide for newly diagnosed patients as well as therapeutic options at the time of recurrence.
Journal Article
Oncogenic effects of miR-10b in glioblastoma stem cells
MicroRNAs and cancer stem cells have emerged as critical players in glioblastoma, one of the deadliest human cancers. In this study, we investigated the expression and function of microRNA-10b in glioblastoma cells and stem cells. An analysis of The Cancer Genome Atlas data revealed a correlation between high miR-10b levels and poor prognosis in glioblastoma patients. We measured the levels of miR-10b and found that it is upregulated in human glioblastoma tissues, glioblastoma cell and stem cell lines as compared to normal human tissues or astrocytes. Inhibition of miR-10b with a specific antagomir inhibited the proliferation of glioblastoma established and stem cell lines. Inhibition of miR-10b strongly reduced cell invasion and migration in glioblastoma cell and stem cell lines while overexpression of miR-10b induced cell migration and invasion. We also investigated several predicted targets of miR-10b but could not verify any of them experimentally. Additionally, miR-10b inhibition significantly decreased the in vivo growth of stem cell-derived orthotopic GBM xenografts. Altogether, our findings confirm the oncogenic effects of miR-10b in GBM cells and show for the first time a role of this microRNA in GBM stem cells. Targeting miR-10b might therefore inhibit glioblastoma stem cells, which are thought to be at the origin of glioblastoma and to contribute its recurrence and resistance to therapy.
Journal Article
A Sociology of Jurisprudence
Niklas Luhmann's sociological theory treats law, along with politics, economics, media and ethics, as systems of communication. His theory not only offers profound and novel insights into the character of the legal system in modern society, but also provides an explanation for the role of jurisprudence as part of that legal system. In this work the authors seek to explore and develop Luhmann's claim that jurisprudence is part of law's self-description; a part of the legal system which, as a particular kind of legal communication, orientates legal operations by explaining law to itself. This approach has the potential to illuminate many of the interminable debates amongst and between different schools of jurisprudence on topics such as the origin and/or source of law, the nature of law's determinacy or indeterminacy, and the role of justice. The authors' introduction to Luhmann's systems theory concentrates on the concept of closure and the distinct disposition of law's openness to its environment. From this beginning, the book goes on to offer a sustained and methodical application of systems theory to some of the traditional forms of jurisprudence: natural law and its relationship with legal positivism, Dworkin's version of natural law, Kelsen's version of legal positivism, and Critical Legal Studies. This application of systems theory alters our perception of jurisprudence and better enables us to understand its role within law.
eBook