Overexpression of RNA-binding protein CELF1 prevents apoptosis and destabilizes pro-apoptotic mRNAs in oral cancer cells.

CELF1 RNA-binding protein, otherwise called CUGBP1, associates and coordinates the degradation of GU-rich element (GRE) containing mRNA's encoding factors important for cell growth, migration and apoptosis. Although many substrates of CELF1 have been identified, the biological significance of CELF1-mediated mRNA decay remains unclear. As the processes modulated by CELF1 are frequently disrupted in cancer, we investigated the expression and role of CELF1 in oral squamous cancer cells (OSCCs). We determined that CELF1 is reproducibly overexpressed in OSCC tissues and cell lines. Moreover, depletion of CELF1 reduced proliferation and increased apoptosis in OSCCs, but had negligible effect in non-transformed cells. We found that CELF1 associates directly with the 3'UTR of mRNAs encoding the pro-apoptotic factors BAD, BAX and JunD and mediates their rapid decay. Specifically, 3'UTR fragment analysis of JunD revealed that the GRE region is critical for binding with CELF1 and expression of JunD in oral cancer cells. In addition, silencing of CELF1 rendered BAD, BAX and JunD mRNAs stable and increased their protein expression in oral cancer cells. Taken together, these results support a critical role for CELF1 in modulating apoptosis and implicate this RNA-binding protein as a cancer marker and potential therapeutic target.

Office-Based Multilevel Radiofrequency Ablation for Mild-to-Moderate Obstructive Sleep Apnea.

Objective: Investigate multilevel radiofrequency ablation (RFA) as an alternative therapy for patients with mild-to-moderate obstructive sleep apnea (OSA). Study Design: Prospective, open-label, single-arm, nonrandomized clinical trial. Setting: Multicenter academic and private clinics. Methods: Patients with mild-to-moderate OSA (apnea-hypopnea index [AHI] 10-30; body mass index ≤ 32) were treated with 3 sessions of office-based RFA to the soft palate and tongue base. The primary outcome was a change in the AHI and oxygen desaturation index (ODI 4%). Secondary outcomes included subjective sleepiness level; snoring level; and sleep-related quality of life. Results: Fifty-six patients were enrolled, with 43 (77%) completing the study protocol. Following 3 sessions of office-based RFA to the palate and base of the tongue, the mean AHI decreased from 19.7 to 9.9 (p = .001), while the mean ODI (4%) decreased from 12.8 to 8.4 (p = .005). Mean Epworth Sleepiness Scale scores declined from 11.2 (±5.4) to 6.0 (±3.5) (p = .001), while Functional Outcomes of Sleep Questionnaire scores improved from a mean of 14.9 at baseline to 17.4 (p = .001). The mean visual analog scale snoring scale was reduced from 5.3 (±1.4) at baseline to 3.4 (±1.6) at 6 months posttherapy (p = .001). Conclusion: Office-based, multilevel RFA of the soft palate and base of the tongue is a safe and effective treatment option with minimal morbidity for properly selected patients with mild-to-moderate OSA who are intolerant or refuse continuous positive airway pressure therapy.

Botox for the prevention of radiation-induced Sialadenitis and xerostomia in head and neck cancer patients: A pilot study.

BACKGROUND: To determine the safety of Botox and its potential effect on alleviating radiation therapy (RT)-induced sialadenitis in head and neck cancer patients. METHODS: Twenty patients with stage III/IV head and neck cancer were randomized to receive Botox or saline injections into both submandibular glands (SMG). There were three visits: one before RT (V1); 1 week after RT (V2); and 6 weeks after RT (V3), each of which included saliva collection, a 24-h dietary recall, and a quality-of-life survey. RESULTS: No adverse events were observed. While the control group was much older, the Botox group more commonly underwent induction chemotherapy compared with controls. From V1 to V2, salivary flow decreased in both groups, but only in the control group from V1 to V3. CXCL-1 (GRO), a neutrophil chemoattractant, was lower in the Botox group compared with the control group at V3. CONCLUSION: Botox can be safely administered to the salivary glands prior to external beam radiation without observed complications or side-effects. After an initial reduction in salivary flow following RT, the Botox group showed lack of further flow reduction compared with controls. The inflammatory marker CXCL 1, which was reduced in the in Botox group at V3, may be a candidate for further studies of radiation-induced sialadenitis.

Caspase-mediated cleavage of RNA-binding protein HuR regulates c-Myc protein expression after hypoxic stress.

Altered expression of RNA-binding proteins modulates gene expression in association with mRNAs encoding many proto-oncogenes, cytokines, chemokines, and proinflammatory factors. Hu antigen R (HuR), a ubiquitously expressed protein, controls a range of cellular functions such as tumor progression, apoptosis, invasion, and metastasis by stabilizing the AU-rich element located at the 3'-untranslated region (UTR) of target mRNAs. Although significant progress has been made in understanding HuR regulation in gene expression, little is known about how HuR undergoes post-translational modifications and recruits target mRNAs during hypoxic stress. Here, we report that during CoCl(2)-induced hypoxic stress, HuR is significantly overexpressed and undergoes caspase-dependent cleavage in head and neck squamous cell carcinoma cells. Unexpectedly, the HuR-cleavage product 1 (HuR-CP1) was found to strongly associate with the 3'-UTR of c-myc mRNA and block mRNA translation. The binding efficiency of HuR to the 3'-UTR of c-myc mRNA was confirmed using ribonucleoprotein immunoprecipitation and site-directed mutagenesis at the AU-rich element sequences of the c-myc mRNA. Overexpression of a non-cleavable isoform, HuR-D226A, revealed a potent dominant-negative effect, repressing cleavage of endogenous HuR and promoting cell viability. Surprisingly, under hypoxia, siRNA knockdown of HuR elevated c-Myc protein expression. These findings suggest an important role for HuR in hypoxia, and we may have revealed a novel post-transcriptional mechanism that controls c-Myc expression in oral cancer progression.

Phenotypes of Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) is a multisystem breathing disorder associated with increased morbidity and mortality. Clinical and operative assessment tools improve surgical approaches to treat airway obstruction. The primary sites of anatomic obstruction are at the levels of the nasal, palatal, and hypopharyngeal airway. The literature suggests a relationship between reduced neuromuscular tone and the age-related increase in OSA prevalence for normal-weight adults. Pharyngeal soft tissue collapse due to reduced airway pressure is defined as the critical closing pressure. Respiratory biochemistry homeostasis is an additional factor in maintaining airway patency.

Salivary and lacrimal dysfunction after radioactive iodine for differentiated thyroid cancer: American Head and Neck Society Endocrine Surgery Section and Salivary Gland Section joint multidisciplinary clinical consensus statement of otolaryngology, ophthalmology, nuclear medicine and endocrinology.

BACKGROUND: Postoperative radioactive iodine (RAI) administration is widely utilized in patients with differentiated thyroid cancer. While beneficial in select patients, it is critical to recognize the potential negative sequelae of this treatment. The prevention, diagnosis, and management of the salivary and lacrimal complications of RAI exposure are addressed in this consensus statement. METHODS: A multidisciplinary panel of experts was convened under the auspices of the American Head and Neck Society Endocrine Surgery and Salivary Gland Sections. Following a comprehensive literature review to assess the current best evidence, this group developed six relevant consensus recommendations. RESULTS: Consensus recommendations on RAI were made in the areas of patient assessment, optimal utilization, complication prevention, and complication management. CONCLUSION: Salivary and lacrimal complications secondary to RAI exposure are common and need to be weighed when considering its use. The recommendations included in this statement provide direction for approaches to minimize and manage these complications.

Diagnostic Value of RAS Mutations in Indeterminate Thyroid Nodules.

Objectives To determine the diagnostic value of HRAS, KRAS, and NRAS mutations in fine-needle aspiration biopsies of thyroid nodules that are nondiagnostic on cytology. Data Sources PubMed, Scopus, Embase, CINAHL. Review Methods Two authors independently searched the data sources. To be included, studies reported the RAS mutational status and postoperative histopathologic diagnosis of nodules that exhibited indeterminate cytology after fine-needle aspiration biopsy. Data were extracted to calculate sensitivity, specificity, and positive/negative predictive values of any HRAS, KRAS, or NRAS mutation. A meta-analysis was performed to generate pooled values for each parameter. Results A total of 7 studies with a combined 1025 patients met inclusion criteria. The pooled sensitivity of a RAS mutation for detecting cancer was 0.343 (95% confidence interval [95% CI], 0.198-0.506), while the pooled specificity was 0.935 (95% CI, 0.882-0.973). The weighted averages for positive predictive value and negative predictive value were 78.0% and 64.0%, respectively, with 68.0% accuracy. The positive likelihood ratio was 4.235 (95% CI, 1.506-11.910), and the negative likelihood ratio was 0.775 (95% CI, 0.630-0.953). Conclusion Our data suggest that testing for any RAS mutation is unlikely to change the clinical management of thyroid nodules that have indeterminate cytology. While a RAS mutation may rule in malignancy, the sensitivity of testing is low enough to merit further mutational analysis, repeat fine-needle aspiration, or surgical excision, even in the presence of a negative test.