Epigenetics explained: a topic “primer” for the epilepsy community by the ILAE Genetics/Epigenetics Task Force

Epigenetics refers broadly to processes that influence medium to long‐term gene expression by changing the readability and accessibility of the genetic code. The Neurobiology Commission of the International League Against Epilepsy (ILAE) recently convened a Task Force to explore and disseminate advances in epigenetics to better understand their role and intersection with genetics and the neurobiology of epilepsies and their co‐morbidities, and to accelerate translation of these findings into the development of better therapies. Here, we provide a topic primer on epigenetics, explaining the key processes and findings to date in experimental and human epilepsy. We review the growing list of genes with epigenetic functions that have been linked with epilepsy in humans. We consider potential practical applications, including using epigenetic signals as biomarkers for tissue‐ and biofluid‐based diagnostics and the prospects for developing epigenetic‐based treatments for epilepsy. We include a glossary of terms, FAQs and other supports to facilitate a broad understanding of the topic for the non‐expert. Last, we review the limitations, research gaps and the next challenges. In summary, epigenetic processes represent important mechanisms controlling the activity of genes, providing opportunities for insight into disease mechanisms, biomarkers and novel therapies for epilepsy.     

Postoperative development of sarcopenia is a strong predictor of a poor prognosis in patients with adenocarcinoma of the esophagogastric junction and upper gastric cancer

Background

There were few studies assessed the postoperative sarcopenia in patients with cancers. The objective of present study was to assess whether postoperative development of sarcopenia could predict a poor prognosis in patients with adenocarcinoma of esophagogastric junction, (AEG) and upper gastric cancer (UGC).

Binding profile of SM-9018, a novel antipsychotic candidate

The present study employed various receptor-binding assays to clarify the biochemical characteristics of SM-9018. SM-9018 possessed very high affinity for 5-HT2, D2 and 5-HT1A receptors (Ki = 0.61, 1.4 and 2.9 nM, respectively), and it had moderate affinity for alpha 1 and D1 receptors (Ki = 17 and 41 nM, respectively). However, SM-9018 had only negligible affinity for alpha 2, opiate, glutamate, phencyclidine, benzodiazepine and GABAA receptors. These results suggest that SM-9018 may be a novel antipsychotic agent with binding affinity for 5-HT2 and 5-HT1A receptors.     

Gliomatosis cerebri with good prognosis

A 52-year-old man was admitted to our clinic with severe headache and bilateral papilledema. Magnetic resonance (MR) images on admission demonstrated diffuse swelling of the cerebral cortex without formation of a tumor mass. Biopsy revealed diffuse infiltration with neoplastic glial cells. After radiation and chemotherapy, the MR images returned to normal. The morphological and neurological features of the present case met the criteria for gliomatosis cerebri. However, this patient showed an unusually good response to radiation and chemotherapy.     

Modifying Effects of Various Chemicals on Preneoplastic and Neoplastic Lesion Development in a Wide-spectrum Organ Carcinogenesis Model Using F344 Rats

Modifying potentials of various chemicals on tumor development were investigated in a wide-spectrum organ carcinogenesis model using male F344/DuCrj rats. The animals were treated with N-nitroso-diethylamine (100 mg/kg body weight, ip, single injection at the commencement of the study), N-methyl-N-nitrosourea (20 mg/kg body weight, ip, 4 times during weeks 1 and 2) and N-bis(2-hydroxypropyl)nitrosamine (0.1% in drinking water, during weeks 3 and 4) for multi-organ initiation and then were given one of 14 test chemicals including 6 hepatocarcinogens, 7 non-hepatocarcinogens and 1 non-carcinogen, or basal diet for 16 weeks. All rats were killed at the end of week 20, and the major organs were carefully examined for preneoplastic and neoplastic lesions. Immunohistochemical demonstration of glutathione S -transferase-positivc foci was also used for quantitative assessment of liver preneoplastic lesion development. Modifying effects were shown for 11 out of 14 test agents in the liver, forestomach, glandular stomach, lung, urinary bladder or thyroid, 7 of them targeting more than two organs. This was the first demonstration to our knowledge that cloflbrate possesses enhancing potential for urinary bladder carcinogenesis and an inhibiting effect on thyroid carcinogenesis. Caprolactam showed no effect in any organ, in agreement with its established inactivity. The results indicated that the system could be reliably applied as a medium-term multiple organ bioassay for assessment of the modification potential of test agents in unknown target sites.     

Subretinal neovascularisation and snow banking in a case of sarcoidosis: case report.

A 49-year-old Japanese man presented with chronic granulomatous uveitis in his left eye. Later he developed macular subretinal neovascularisation. The chest x-ray showed bilateral hilar lymphadenopathy. Bronchoscopy and gallium-67 scanning were positive, PPD skin test negative, and serum angiotensin converting enzyme (ACE) levels increased. Ophthalmoscopy and fluorescein angiography of the left eye showed perivasculitis, retinochoroidal exudates, snow banking, and vitreous opacity. On these findings, the diagnosis of sarcoidosis was made. Treatment was based on topical corticosteroids, mydriatics, beta blockers, and oral carbonic anhydrase inhibitors. After 15 months the visual acuity decreased in the left eye, and a neovascular membrane was observed in the macula. Fluorescein angiography confirmed subretinal neovascularisation. Almost two years later the patient still has the neovascular membrane in his left eye.     

Electroencephalographic study on the central action of a new anxiolytic: 3a alpha, 4 beta, 7 beta, 7a alpha-hexahydro-2-(4-(4-(2-pyrimidinyl)-1- piperazinyl)-butyl)-4, 7-methano-1H-isoindole-1, 3(2H)-dione dihydrogen citrate (SM-3997)

Electroencephalographic (EEG) studies were performed to examine the effects of SM-3997 on the spontaneous EEG, EEG arousal responses, recruiting responses and hippocampal afterdischarges in rabbits and the spontaneous EEG in chronically electrode-implanted rats. In acute experiments using rabbits, SM-3997 at doses of 1-3 mg/kg, i.v., produced low-voltage fast waves in cortical EEG and slow waves with reduction of the amplitude in hippocampal EEG. The drug at doses of 1-3 mg/kg, i.v., dose-dependently inhibited the threshold stimulus voltages in EEG arousal responses induced by stimulation of the midbrain reticular formation and slightly inhibited the threshold in recruiting responses by stimulation of the centromedian nucleus of the thalamus. However, the cortical and hippocampal afterdischarges induced by hippocampal stimulation remained unaffected by SM-3997 at doses up to 3 mg/kg, i.v., while they were inhibited by diazepam of 1 mg/kg, i.v. In the study using rats in which electrodes were chronically implanted, SM-3997 at doses of 10-30 mg/kg, i.p., also produced low voltage fast waves in cortical EEG and slow waves of reduced amplitude in hippocampal EEG; and it simultaneously caused flat body posture. These results suggest that SM-3997 acts on both the cerebral cortex and hippocampus, inducing much more pronounced inhibition on the midbrain reticular formation-hippocampal system     

Retroperitoneal primary mucinous adenocarcinoma with a mural nodule of anaplastic tumor: a case report and literature review.

A 38-year-old female presented with a lower abdominal mass. During the operation the mass was found to be retroperitoneal and was excised. Gross examination revealed a mucin-containing cystic lesion with a mural nodule. On microscopic examination, the cystic areas were lined by an invasive mucinous adenocarcinoma and the nodule was composed of an anaplastic sarcomatoid tumor that was immunoreactive for cytokeratin. This present case is the 21st example of a retroperitoneal primary mucinous cystadenocarcinoma and the fourth with a mural nodule. Three of four cases with a mural nodule, including our case, had a rapidly fatal outcome.