IMPDH Inhibition Decreases TERT Expression and Synergizes the Cytotoxic Effect of Chemotherapeutic Agents in Glioblastoma Cells.

IMP dehydrogenase (IMPDH) inhibition has emerged as a new target therapy for glioblastoma multiforme (GBM), which remains one of the most refractory tumors to date. TCGA analyses revealed distinct expression profiles of IMPDH isoenzymes in various subtypes of GBM and low-grade glioma (LGG). To dissect the mechanism(s) underlying the anti-tumor effect of IMPDH inhibition in adult GBM, we investigated how mycophenolic acid (MPA, an IMPDH inhibitor) treatment affected key oncogenic drivers in glioblastoma cells. Our results showed that MPA decreased the expression of telomerase reverse transcriptase (TERT) in both U87 and U251 cells, and the expression of O6-methylguanine-DNA methyltransferase (MGMT) in U251 cells. In support, MPA treatment reduced the amount of telomere repeats in U87 and U251 cells. TERT downregulation by MPA was associated with a significant decrease in c-Myc (a TERT transcription activator) in U87 but not U251 cells, and a dose-dependent increase in p53 and CCCTC-binding factor (CTCF) (TERT repressors) in both U87 and U251 cells. In U251 cells, MPA displayed strong cytotoxic synergy with BCNU and moderate synergy with irinotecan, oxaliplatin, paclitaxel, or temozolomide (TMZ). In U87 cells, MPA displayed strong cytotoxic synergy with all except TMZ, acting primarily through the apoptotic pathway. Our work expands the mechanistic potential of IMPDH inhibition to TERT/telomere regulation and reveals a synthetic lethality between MPA and anti-GBM drugs.

Nucleostemin and GNL3L exercise distinct functions in genome protection and ribosome synthesis, respectively.

The mammalian nucleolar proteins nucleostemin and GNL3-like (GNL3L) are encoded by paralogous genes that arose from an ancestral invertebrate gene, GNL3. Invertebrate GNL3 has been implicated in ribosome biosynthesis, as has its mammalian descendent, GNL3L. The paralogous mammalian nucleostemin protein has, instead, been implicated in cell renewal. Here, we found that depletion of nucleostemin in a human breast carcinoma cell line triggers prompt and significant DNA damage in S-phase cells without perturbing the initial step of ribosomal (r)RNA synthesis and only mildly affects the total ribosome production. By contrast, GNL3L depletion markedly impairs ribosome production without inducing appreciable DNA damage. These results indicate that, during vertebrate evolution, GNL3L retained the role of the ancestral gene in ribosome biosynthesis, whereas the paralogous nucleostemin acquired a novel genome-protective function. Our results provide a coherent explanation for what had seemed to be contradictory findings about the functions of the invertebrate versus vertebrate genes and are suggestive of how the nucleolus was fine-tuned for a role in genome protection and cell-cycle control as the vertebrates evolved.

Long-term efficacy and safety of fluphenazine in patients with Tourette syndrome.

OBJECTIVES: Haloperidol and pimozide are the only drugs currently approved by the U.S. Food and Drug Administration for treatment of Tourette syndrome (TS), but their potential side effects, which include tardive dyskinesia (TD), limit their use. METHODS: We performed a retrospective chart review of patients with TS treated with fluphenazine over a 26-year period. RESULTS: Among 268 patients with TS, fluphenazine was initiated at a mean age of 15.8 ± 10.7 years (range, 4.1-70.2) and titrated to an optimal dose of 3.24 ± 2.3 mg/day (range, 0.5-12.0), which was continued for an average of 2.6 ± 3.2 years (range, 0.01-16.8). Marked to moderate improvement was noted in 211 (80.5%). The most common side effects included drowsiness, fatigue, or both, observed in 70 (26.1%) patients. There were no cases of TD. CONCLUSIONS: Fluphenazine appears to be safe and effective in the treatment of TS, and there were no cases of TD in this cohort treated up to 16.8 years.

Assessment of appropriate medication administration for hospitalized patients with Parkinson's disease.

BACKGROUND: For Parkinson's disease (PD) patients, adherence to a regular PD medication schedule is important in achieving optimal symptom control. There are few published studies quantifying PD medication administrations in hospitalized PD patients. METHODS: Hospitalization records for 100 veterans with idiopathic PD and admitted to our center were reviewed to determine the on time rate and contraindicated medication doses. A barcode based computerized medication administration system within the electronic medical record provided information of the exact time the medication was given to a patient. RESULTS: Eighty-nine idiopathic PD patients met study inclusion criteria. Among them, 87 were on levodopa monotherapy or in combination with other PD medications. Two patients were on dopamine agonists only. A total of 3873 doses of PD medications were prescribed during hospitalization. Among 675 incorrect medication administrations, 322 doses were omitted, 300 doses late by ≥ 30 min, and 53 doses given early by ≥ 30 min. Contraindicated medications were prescribed for 19 patients. The correct administration percentage was lower during the first 2 days post-admission compared to subsequent days (mean 74.6% vs. 82.8%) and higher for patients who had neurological consultations (mean 85.5% vs. 76.5%). Correct administration rates were better for patient-based medication schedules (85.6%) than with hospital-based schedules (77.5%), but did not achieve statistical significance. CONCLUSION: Adherence to regular PD medication dosing schedules during hospitalization is problematic, but improves with specialist consultation. Staff involved in the admission process for PD patients should work to safeguard against disruption of the prescribed home dosing schedule.

Applause sign in Parkinsonian disorders and Huntington's disease.

The applause sign has been previously reported to be indicative of neurodegenerative disorders, such as progressive supranuclear palsy (PSP). In order to determine the sensitivity, specificity, and positive predictive value, we tested it in patients with PSP, Parkinson's disease (PD), multiple system atrophy (MSA), corticobasal degeneration (CBD), and Huntington's disease (HD). Subjects were asked to clap three times after demonstration by the examiner. The performance was scored as follows: 3 = claps only three times; 2 = claps four times; 1 = claps 5 to 10 times; 0 = claps >10 times. The clap test was videotaped and rated. Patients with CBD, MSA, and PSP showed significant differences in clap scores compared with normal controls. The test differentiated patients with CBD from those with PD (P < 0.005) and HD (P < 0.005), but failed to discriminate patients with PSP from other parkinsonian groups. The specificity of the applause sign is 100% in distinguishing parkinsonian patients from normal subjects with the highest sensitivity in CBD patients. We concluded that the applause sign is highly specific for parkinsonian disorders but it is not a specific sign for PSP; it appears to be most sensitive for CBD.

Runner's dystonia.

Adult-onset focal dystonia in the upper limbs is well characterized whereas such dystonia has been rarely reported in the lower limbs, especially in proximal parts. When such focal dystonia occurs in an athlete it is often wrongly attributed to an orthopedic disorder. We present five cases, three female and two male with mean age of 44.6+/-10.43 years, mean age at onset of 37.4+/-10.33 years, and mean duration of symptoms for 7.2+/-4.44 years, who initially noted dystonia of one leg during long-distance running. The clinical features of dystonia in these long-distance runners overlap with those of more recognizable forms of focal dystonia including relief with sensory or motor "tricks". They also share features with paroxysmal dyskinesia and carbamazepine markedly ameliorated the symptoms at least in one patient. One patient benefited from an oral anticholinergic, one from levodopa, and another two patients benefited from repeat botulinum toxin injections. Our patients differed from the typical childhood-onset leg dystonia, such as the DYT1 dystonia, in that there was no family history of dystonia and the leg dystonia remained focal without spreading to other body parts. Two of our patients had prior injury to the affected leg within 1 year prior to the onset of the dystonia, raising the possibility of peripherally-induced dystonia. We draw attention to this rare, disabling, adult-onset focal dystonia involving proximal lower limbs. When recognized early, it may be treated effectively with either anticholinergic drugs, anticonvulsants, levodopa, or botulinum toxin injections.