INTRODUCTION: Hepatic encephalopathy (HE) is associated with marked increases in morbidity and mortality for patients with cirrhosis. We aimed to determine the risk of and predictors for HE in contemporary patients. METHODS: We prospectively enrolled 294 subjects with Child A-B (70% Child A) cirrhosis and portal hypertension without previous HE from July 2016 to August 2018. The primary outcome was the development of overt HE (grade >2). We assessed the predictive power of model for end-stage liver disease-sodium (MELD-Na) score, the Inhibitory Control Test, the Sickness Impact Profile score, and the Bilirubin–Albumin–Beta-Blocker–Statin score. We also derived a novel predictive model incorporating MELD-Na score, impact of cirrhosis on daily activity (Likert 1–9), frailty (chair-stands per 30 seconds), and health-related quality of life (Short-Form 8, 0–100). RESULTS: The cohort's median age was 60 years, 56% were men, and the median MELD-Na score was 9. During a follow-up of 548 ± 281 days, 62 (21%) had incident overt HE with 1-year probability of 14% ± 2%, 10% ± 2%, and 25% ± 5% for Child A and B. The best model for predicting the risk of overt HE included MELD-Na, Short-Form 8, impact on activity rating, and chair-stands within 30 seconds. This model—MELDNa-Actvity-Chairstands-Quality of Life Hepatic Encephalopathy Score—offered an area under the receiver operating curve (AUROC) for HE development at 12 months of 0.82 compared with 0.55, 0.61, 0.70, and 0.72 for the Inhibitory Control Test, Sickness Impact Profile, Bilirubin–Albumin–Beta-Blocker–Statin, and MELD-Na, respectively. The AUROC for HE-related hospitalization was 0.92. DISCUSSION: This study provides the incidence of HE in a well-characterized cohort of contemporary patients. Bedside measures such as activity, quality of life, and physical function accurately stratified the patient's risk for overt HE.
We have recently synthesized a peptide called Disruptin, which comprised the SVDNPHVC segment of the epidermal growth factor receptor (EGFR) that inhibits binding of heat shock protein 90 (Hsp90) to the EGFR and EGF-dependent EGFR dimerization to cause EGFR degradation. The effect is specific for EGFR versus other Hsp90 client proteins [Ahsan et al.: (2013). Destabilization of the epidermal growth factor receptor (EGFR) by a peptide that inhibits EGFR binding to heat shock protein 90 and receptor dimerization. J Biol Chem288, 26879-26886]. Here, we show that Disruptin decreases the clonogenicity of a variety of EGFR-dependent cancer cells in culture but not of EGFR-independent cancer or noncancerous cells. The selectivity of Disruptin toward EGFR-driven cancer cells is due to the high level of EGF stimulation of EGFR in EGFR-dependent tumor cells relative to normal cells. When administered by intraperitoneal injection into nude mice bearing EGFR-driven human tumor xenografts, Disruptin causes extensive degradation of EGFR in the tumor but not in adjacent host tissue. Disruptin markedly inhibits the growth of EGFR-driven tumors without producing the major toxicities caused by the Hsp90 inhibitor geldanamycin or by cisplatin. These findings provide proof of concept for development of a new Disruptin-like class of antitumor drugs that are directed specifically against EGFR-driven tumors.
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