Bevacizumab plus Irinotecan,Fluorouracil,and Leucovorin for Metastatic Colorectal Cancer

Arginine Methylation: The Coming of Age

Post-translational arginine methylation is responsible for regulation of many biological processes. The protein arginine methyltransferase 5 (PRMT5, also known as Hsl7, Jbp1, Skb1, Capsuleen, or Dart5) is the major enzyme responsible for mono- and symmetric dimethylation of arginine. An expanding literature demonstrates its critical biological function in a wide range of cellular processes. Histone and other protein methylation by PRMT5 regulate genome organization, transcription, stem cells, primordial germ cells, differentiation, the cell cycle, and spliceosome assembly. Metazoan PRMT5 is found in complex with the WD-repeat protein MEP50 (also known as Wdr77, androgen receptor coactivator p44, or Valois). PRMT5 also directly associates with a range of other protein factors, including pICln, Menin, CoPR5 and RioK1 that may alter its subcellular localization and protein substrate selection. Protein substrate and PRMT5–MEP50 post-translation modifications induce crosstalk to regulate PRMT5 activity. Crystal structures of C. elegans PRMT5 and human and frog PRMT5–MEP50 complexes provide substantial insight into the mechanisms of substrate recognition and procession to dimethylation. Enzymological studies of PRMT5 have uncovered compelling insights essential for future development of specific PRMT5 inhibitors. In addition, newly accumulating evidence implicates PRMT5 and MEP50 expression levels and their methyltransferase activity in cancer tumorigenesis, and, significantly, as markers of poor clinical outcome, marking them as potential oncogenes. Here, we review the substantial new literature on PRMT5 and its partners to highlight the significance of understanding this essential enzyme in health and disease.

The PRMT5 arginine methyltransferase: many roles in development, cancer and beyond.

In many plant species, gene dosage is an important cause of phenotype variation. Engineering gene dosage, particularly in polyploid genomes, would provide an efficient tool for plant breeding. The hexaploid oilseed crop Camelina sativa, which has three closely related expressed subgenomes, is an ideal species for investigation of the possibility of creating a large collection of combinatorial mutants. Selective, targeted mutagenesis of the three delta-12-desaturase (FAD2) genes was achieved by CRISPR-Cas9 gene editing, leading to reduced levels of polyunsaturated fatty acids and increased accumulation of oleic acid in the oil. Analysis of mutations over four generations demonstrated the presence of a large variety of heritable mutations in the three isologous CsFAD2 genes. The different combinations of single, double and triple mutants in the T3 generation were isolated, and the complete loss-of-function mutants revealed the importance of delta-12-desaturation for Camelina development. Combinatorial association of different alleles for the three FAD2 loci provided a large diversity of Camelina lines with various lipid profiles, ranging from 10% to 62% oleic acid accumulation in the oil. The different allelic combinations allowed an unbiased analysis of gene dosage and function in this hexaploid species, but also provided a unique source of genetic variability for plant breeding.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/pbi.12671

Selective gene dosage by CRISPR-Cas9 genome editing in hexaploid Camelina sativa

Object There is limited information on the relationship between patient age and the clinical benefit of resection in patients with glioblastoma. The purpose of this study was to use a population-based database to determine whether patient age influences the frequency that gross-total resection (GTR) is performed, and also whether GTR is associated with survival difference in different age groups. Methods The authors identified 20,705 adult patients with glioblastoma in the Surveillance, Epidemiology, and End Results (SEER) registry (1998–2009). Surgical practice patterns were defined by the categories of no surgery, subtotal resection (STR), and GTR. Kaplan-Meier and multivariate Cox regression analyses were used to assess the pattern of surgical practice and overall survival. Results The frequency that GTR was achieved in patients with glioblastoma decreased in a stepwise manner as a function of patient age (from 36% [age 18–44 years] to 24% [age ≥ 75]; p < 0.001). For all age groups, glioblastoma patien...

Gross-total resection outcomes in an elderly population with glioblastoma: a SEER-based analysis

Protein arginine methyltransferase 5 (PRMT5) catalyzes the formation of ω-NG,N'G-symmetric dimethylarginine residues on histones as well as other proteins. These modifications play an important role in cell differentiation and tumor cell growth. However, the role of PRMT5 in human glioma cells has not been characterized. In this study, we assessed protein expression profiles of PRMT5 in control brain, WHO grade II astrocytomas, anaplastic astrocytomas, and glioblastoma multiforme (GBM) by immunohistochemistry. PRMT5 was low in glial cells in control brain tissues and low grade astrocytomas. Its expression increased in parallel with malignant progression, and was highly expressed in GBM. Knockdown of PRMT5 by small hairpin RNA caused alterations of p-ERK1/2 and significantly repressed the clonogenic potential and viability of glioma cells. These findings indicate that PRMT5 is a marker of malignant progression in glioma tumors and plays a pivotal role in tumor growth.

/pdf/expression-of-prmt5-correlates-with-malignant-grade-in-3gxmgklorl.pdf

Expression of PRMT5 correlates with malignant grade in gliomas and plays a pivotal role in tumor growth in vitro

Glioblastoma multiforme (GBM) causes significant neurological morbidity and short survival times. Brain invasion by GBM is associated with poor prognosis. Recent clinical trials of bevacizumab in newly-diagnosed GBM found no beneficial effects on overall survival times; however, the baseline health-related quality of life and performance status were maintained longer in the bevacizumab group and the glucocorticoid requirement was lower. Here, we construct a clinical-scale model of GBM whose predictions uncover a new pattern of recurrence in 11/70 bevacizumab-treated patients. The findings support an exception to the Folkman hypothesis: GBM grows in the absence of angiogenesis by a cycle of proliferation and brain invasion that expands necrosis. Furthermore, necrosis is positively correlated with brain invasion in 26 newly-diagnosed GBM. The unintuitive results explain the unusual clinical effects of bevacizumab and suggest new hypotheses on the dynamic clinical effects of migration by active transport, a mechanism of hypoxia-driven brain invasion.

/pdf/effects-of-anti-angiogenesis-on-glioblastoma-growth-and-1rhgmdwv0p.pdf

Effects of Anti-Angiogenesis on Glioblastoma Growth and Migration: Model to Clinical Predictions

/pdf/hypoxia-angiogenesis-and-mechanisms-for-invasion-of-s1ny9diyht.pdf

Hypoxia, Angiogenesis and Mechanisms for Invasion of Malignant Gliomas

OBJECTIVE: To highlight the historical landmarks of EMG and NCS development by reviewing the major discoveries and publications of Bronk, Denny-Brown, Larrabee and Lambert. BACKGROUND: In 1771, Galvani Showed that electrical stimulation of muscular tissue produces contraction and force. This electrical response was not quantified until the development of improved recording equipment including the cathode ray oscilloscope by Gasser and Erlanger in 1922 and the amplifier and the oscillograph by Matthews in 1928. The first modern EMG machine was constructed by Jasper in 1942 at McGill University, Montreal, Canada. DESIGN/METHODS: Review of the original publications of Bronk, Denny-Brown, Larrabee, Lambert and their colleagues. RESULTS: In 1929, Adrian and Bronk devised a method to record a single motor unit action potential (MUAP) in human subjects by connecting concentric and bipolar needle electrodes to an amplifier and a loud speaker. In 1938, Denny-Brown and Pennybacker recorded and described fasciculations, or action potentials of single contracting or spontaneously firing motor units. They also separated fasciculations from the action potentials of single dennervated muscle fibers and thus described fibrillations. Toward the end of World War II, Larrabee, Hodes and German began measuring the combined potential of individual muscle fibers from the surface of the muscle after stimulating the supplying nerve percutaneously; later known as compound muscle action potential (CMAP). They also quantified the differences in CMAP waveforms when stimulating above and below the site of peripheral nerve injury in war victims. In 1957, Lambert and Eaton described the electrophysiologic features of a newly recognized disease they called the myasthenic syndrome sometimes associated with lung carcinoma. CONCLUSIONS: Bronk and Denny-Brown should be credited for characterizing the normal and abnormal MUAPs respectively. Larrabee and Hodes were the first to generate and record CMAP. Lambert and Eaton differentiated pre- from post-synaptic neuromuscular transmission disorders. Disclosure: Dr. Kazamel has nothing to disclose. Dr. Province has nothing to disclose. Dr. Alsharabati has nothing to disclose. Dr. Oh has nothing to disclose.

History of Electromyography (EMG) and Nerve Conduction Studies (NCS): A Tribute to the Founding Fathers (P05.259)

https://jamanetwork.com/journals/NEUR/articlepdf/1107905/nim110015_1476_1477.pdf

Paula Province

Papers

Expression of PRMT5 correlates with malignant grade in gliomas and plays a pivotal role in tumor growth in vitro

Effects of Anti-Angiogenesis on Glioblastoma Growth and Migration: Model to Clinical Predictions

Hypoxia, Angiogenesis and Mechanisms for Invasion of Malignant Gliomas

History of Electromyography (EMG) and Nerve Conduction Studies (NCS): A Tribute to the Founding Fathers (P05.259)

Pontine Ring-Enhancing Glioblastoma Multiforme–Like Fungal Abscess