Zerumbone increases oxidative stress in a thiol-dependent ROS-independent manner to increase DNA damage and sensitize colorectal cancer cells to radiation.

Locally advanced rectal cancers are treated with neoadjuvant chemoradiation therapy followed by surgery. In a minority (~20%) of patients, no tumor is present at the time of surgery; these patients with a complete pathologic response (pathCR) to neoadjuvant therapy have better treatment outcomes. Unfortunately, the inherent radioresistance of colorectal cancer (CRC) cells dictates that the majority of patients do not achieve a pathCR. Efforts to improve these odds have fueled the search for novel, relatively less-toxic radiosensitizers with distinct molecular mechanism(s) and broad-spectrum anticancer activities. Here, we use zerumbone, a sesquiterpene from the edible ginger (Zingiber zerumbet Smith), to enhance radiosensitivity of CRC cells. Short exposure to zerumbone (7 h) profoundly sensitized CRC cells, independent of their p53 or k-RAS status. Zerumbone enhanced radiation-induced cell cycle arrest (G2/M), increased radiation-induced apoptosis, but induced little apoptosis by itself. Zerumbone significantly enhanced radiation-induced DNA damage, as evident by delayed resolution of post-irradiation nuclear γH2AX foci, whereas zerumbone treatment alone did not induce γH2AX foci formation. Zerumbone pretreatment inhibited radiation-induced nuclear expression of DNA repair proteins ataxia-telangiectasia mutated (ATM) and DNA-PKcs. Interestingly, zerumbone-mediated radiosensitization did not involve reactive oxygen species (ROS), but was mediated through depletion of cellular glutathione (GSH). Ability of only thiol-based antioxidants to abrogate zerumbone-mediated radiosensitization further corroborated this hypothesis. The α,ß-unsaturated carbonyl group in zerumbone was found to be essential for its bioactivity as zerumbone analog α-Humulene that lacks this functional group, could neither radiosensitize CRC cells, nor deplete cellular GSH. Our studies elucidate novel mechanism(s) of zerumbone's ability to enhance CRC radiosensitivity.

Palinacousis--evidence to suggest a post-ictal phenomenon.

INTRODUCTION: Palinacousis is a paroxysmal auditory illusion in which perseveration of an external auditory stimulus occurs after cessation of the stimulus. The subjects recognize the illusory nature of this experience, which is often a fragment of the last sentence they heard. Palinacousis has been reported in only a few documented cases. It has been described as an aura, a component of complex partial seizures, and a post-ictal event. We put forward evidence demonstrating palinacousis as a post-ictal event. CASE: A 68-year-old woman presented with an acute sensory aphasia, and an EEG showed frequent epileptiform discharges from the left temporo-parietal region. MRI showed an enhancing mass in the left inferior parietal lobule that was consistent with a metastasis. A CT scan of the thorax later showed an enhancing mass in the left lung that was determined to be an invasive non-small cell carcinoma. Treatment with levetiracetam resulted in loss of epileptiform activity on EEG and resolution of aphasia, but soon afterward, she started complaining of recurrent auditory illusions in her right ear. These consisted of phrases from the ends of sentences she heard. Continuous EEG monitoring during her auditory symptoms showed intermittent left temporal slowing but no epileptiform discharges or electrographic seizures. An FDG-PET scan with the glucose uptake phase during episodes of auditory illusions revealed hypometabolism of bilateral medial temporal cortices and increased uptake in the metastatic tumor. REVIEW OF LITERATURE: A systematic review identified 14 cases with palinacousis since 1981. Cases prior to that were excluded due to the lack of sufficient data. DISCUSSION: We propose that palinacousis is a "negative" phenomenon, at least in some individuals. It occurs with a loss of function of a region of the brain that normally suppresses auditory perseveration.

Preclinical antitumor efficacy evaluation of dendrimer-based methotrexate conjugates.

Our previous studies have demonstrated the in-vitro and in-vivo targeting of a generation-5 (G5) dendrimer-based multifunctional conjugate, which used folic acid (FA) as the targeting agent and methotrexate (MTX) as the chemotherapeutic drug. For the synthesized G5-FA-MTX nanodevice conjugate to be clinically applicable as a cancer therapeutic drug, it is important that the compound elicits cytotoxicity specifically and consistently. The aim of this work was to evaluate four independently synthesized batches of G5-FA-MTX conjugates for their cytotoxic potential and specificity. For determination of specificity, we have used a unique 'coculture' assay in which FA receptor-positive and FA receptor-negative cells were cultured together and have examined the preferential killing of the former. The results of our study show the batch-to-batch consistency and specificity of the G5-FA-MTX nanodevice in the preferential killing of FA receptor-positive cells. The coculture assay shows the consistency of the four different G5-FA-MTX conjugate lots in the specific killing of targeted cells. Further in-vivo studies are, however, necessary to prove the clinical potential of this targeted therapeutic nanodevice.