Purpose To develop a clinically relevant model system to study head and neck squamous cell carcinoma (HNSCC), we have established and characterized a direct-from-patient, tumorgraft model of Human Papillomavirus (HPV)-positive and HPV-negative cancers. Experimental Design Patients with newly diagnosed or recurrent HNSCC were consented for donation of tumor specimens. Surgically obtained tissue was implanted subcutaneously into immunodeficient mice. During subsequent passages, both formalin-fixed/paraffin embedded as well as flash frozen tissues were harvested. Tumors were analyzed for a variety of relevant tumor markers. Tumor growth rates and response to radiation, cisplatin, or cetuximab were assessed and early passage cell strains were developed for rapid testing of drug sensitivity. Results Tumorgrafts have been established in 22 of 26 patients to date. Significant diversity in tumorgraft tumor differentiation was observed with good agreement in degree of differentiation between patient tumor and tumorgraft (Kappa 0.72). Six tumorgrafts were HPV-positive on the basis of p16 staining. A strong inverse correlation between tumorgraft p16 and p53 or Rb was identified (Spearman correlations p=0.085 and p=0.002, respectively). Significant growth inhibition of representative tumorgrafts was demonstrated with cisplatin, cetuximab or radiation treatment delivered over a two-week period. Early passage cell strains showed high consistency in response to cancer therapy between tumorgraft and cell strain. Conclusions We have established a robust human tumorgraft model system for investigating HPV-positive and HPV-negative HNSCC. These tumorgrafts show strong correlation with the original tumor specimens and provide a powerful resource for investigating mechanisms of therapeutic response as well as preclinical testing.

KD ICI are most likely virus induced; bronchial cells with ICI contain VLP that share morphologic features among several different RNA viral families. Expedited autopsies and tissue fixation from acute KD fatalities are urgently needed to more clearly ascertain the VLP. These findings are compatible with the hypothesis that the infectious etiologic agent of KD may be a "new" RNA virus.

Control of exercising muscle blood flow is a balance between local vasodilatory factors and the increase in global sympathetic vasoconstrictor outflow. Hypoxia has been shown to potentiate the muscle sympathetic nerve response to exercise, potentially limiting the increase in muscle blood flow. Accordingly, we investigated sympathetic restraint to exercising muscle during whole body exercise in hypoxia. Six dogs chronically instrumented with ascending aortic and hindlimb flow probes and a terminal aortic catheter were studied at rest and mild [2.5 miles/h (mph), 5% grade] and moderate (4.0 mph, 10% grade) exercise while breathing room air or hypoxia (Pa(O(2)) approximately 45 mmHg) in the intact control condition and following systemic alpha-adrenergic blockade (phentolamine). Hypoxia caused an increase in cardiac output (CO), hindlimb flow (Flow(L)), and blood pressure (BP), while total (Cond(T)) and hindlimb conductance (Cond(L)) were unchanged at rest and mild exercise but increased with moderate exercise. During both mild and moderate exercise, alpha-blockade in normoxia resulted in significant vasodilation as evidenced by increases in CO (10%), Flow(L) (17%), Cond(T) (33%), Cond(L) (43%), and a decrease in BP (-18%), with the increase in Cond(L) greater than the increase in Cond(T) during mild exercise. Compared with the normoxic response, alpha-blockade in hypoxia during exercise resulted in a significantly greater increase in Cond(T) (59%) and Cond(L) (74%) and a correspondingly greater decrease in BP (-34%) from baseline. These findings indicate that there is considerable hypoxia-induced sympathetic restraint of muscle blood flow during both mild and moderate exercise, which helps to maintain arterial blood pressure in hypoxia.