Osmolytes are organic solutes that change the protein folding landscape shifting the equilibrium towards the folded state. Herein, we use osmolytes to probe the structuring and aggregation of the intrinsically disordered mutant Huntingtin (mHtt) vis-a-vis the pathogenicity of mHtt on transcription factor function and cell survival. Using an inducible PC12 cell model of Huntington’s disease (HD), we show that stabilizing polyol osmolytes drive the aggregation of Htt103QExon1-EGFP from a diffuse ensemble into inclusion bodies (IBs), whereas the destabilizing osmolyte urea does not. This effect of stabilizing osmolytes is innate, generic, countered by urea, and unaffected by HSP70 and HSC70 knockdown. A qualitatively similar result of osmolyte-induced mHtt IB formation is observed in a conditionally immortalized striatal neuron model of HD, and IB formation correlates with improved survival under stress. Increased expression of diffuse mHtt sequesters the CREB transcription factor to repress CREB-reporter gene activity. This repression is mitigated either by stabilizing osmolytes, which deplete diffuse mHtt or by urea, which negates protein–protein interaction. Our results show that stabilizing polyol osmolytes promote mHtt aggregation, alleviate CREB dysfunction, and promote survival under stress to support the hypothesis that lower molecular weight entities of disease protein are relevant pathogenic species in neurodegeneration.

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Objectives To investigate the impact of facility volume on Patient Safety Indicator (PSI) events following transsphenoidal pituitary surgery (TSPS). Study Design Retrospective database review. Setting National Inpatient Sample database (2003-2011). Methods The National Inpatient Sample was queried for TSPS cases from 2003 to 2011. Facility volume was defined by tertile of average annual number of TSPS procedures performed. PSIs, based on in-hospital complications identified by the Agency of Healthcare Research and Quality, and poor outcomes, such as mortality and tracheostomy, were analyzed. Results An overall 16,039 cases were included: 804 had ≥1 PSI and 15,235 had none. A greater proportion of male to female (5.8% vs 4.3%) and Black to White (7.0% vs 4.5%) patients experienced PSIs. There was an increased likelihood of poor outcome (odds ratio [OR], 3.1 [95% CI, 2.5-3.7]; P < .001) and mortality (OR, 30.1 [95% CI, 18.5-48.8]; P < .001) with a PSI. The incidence rates of PSIs at low-, intermediate-, and high-volume facilities were 5.7%, 5.1%, and 4.2%, respectively. Odds of poor outcome with PSIs were greater at low-volume facilities (OR, 3.3 [95% CI, 2.4-4.4]; P < .001) vs intermediate (OR, 3.1 [95% CI, 2.1-4.2]; P < .001) and high (OR, 2.5 [95% CI, 1.7-3.8]; P < .001). Odds of mortality with PSIs were greater at high-volume facilities (OR, 43.0 [95% CI, 14.3-129.4]; P < .001) vs intermediate (OR, 40.0 [95% CI, 18.5-86.4]; P < .001) and low (OR, 17.3 [95% CI, 8.0-37.7]; P < .001). Conclusion PSIs were associated with a higher likelihood of poor outcome and mortality following TSPS. Patients who experienced PSIs had a lower risk of poor outcome but increased mortality at higher-volume facilities.

Background Our study investigates the prognostic significance of spindle cell histology on overall survival (OS) of conventional head and neck squamous cell carcinoma (HNSCC). Methods The 2004 to 2017 National Cancer Database was queried for patients with head and neck spindle cell carcinoma (HNSpCC) (n = 1572) or HNSCC (n = 242 697) of the oral cavity, major salivary glands, sinonasal tract, oropharynx, hypopharynx, and larynx treated with curative intent. Results Patients with HNSpCC presented more frequently with higher‐grade tumors and cN0 disease than those with HNSCC (p < 0.001). In the oral cavity, the HR for death for SpCC compared with SCC was 1.33 (p < 0.001). In the oropharynx, the HR for death for SpCC compared with SCC was 1.47 (p = 0.028). Conclusions After adjusting for patient, tumor, and treatment characteristics, SpCC histology had an independent adverse prognostic effect on OS in the oral cavity and oropharynx. SpCC histology does not necessarily portend poorer survival in all HNSCC. Level of Evidence: 4.

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