In the present study, we analyzed 28 squamous cell carcinomas of the head and neck (SCCHN) for mutations in the coding region of TbetaR-II using 'Cold' SSCP and automatic DNA sequencing analyses. Twenty-one percent (6/28) of the SCCHN examined contained TbetaR-II mutations compared with patient-matched normal tissues. These alterations included five missense mutations (A:T-->G:C transitions in codons 250, 401, 448 and 488, and a G:C-->T:A transversion in codon 373), and a 38-bp deletion between nucleotides 1825 to 1862. In addition to these code-altering mutations, one case exhibited a silent mutation (A:T-->G:C transition in codon 451) and three cases contained one of two potential population polymorphisms (codons 354 and 389). In contrast to colon and gastric cancers exhibiting microsatellite instability (MI) or replication errors (RER+), no 'indirect' frameshift mutations were identified within a 10-bp polyadenine repeat present in the TbetaR-II coding sequence. All of the mutations in the present study occurred within the highly conserved serine/threonine kinase domain and represent the first report of such 'direct' TbetaR-II mutations in primary human tumors. In addition, we analyzed a subset of SCCHN and corresponding normal samples for TbetaR-II mRNA expression using semi-quantitative multiplex RT-PCR. Expression of TbetaR-II was decreased by 24% to 74% in 20 of 23 SCCHN (87%) compared with patient-matched normal tissues. Taken together, the results from this study suggest that alterations in the nucleic acid sequence and mRNA expression of TbetaR-II are prevalent events in the development of SCCHN, which may deregulate cell cycle control.
Five volunteers, all with a history of childhood asthma that had persisted, though at a reduced severity and incidence, through their teens to the present, performed six treadmill runs on separate days for 6 min at 80% of VO2 max followed by 20 min of recovery. Two trials were completed under each of the following conditions: normal, positive end-expiratory pressure breathing (PEEP) during the work, and PEEP post-exercise. For each trial, forced vital capacity maneuvers (FVC) were completed twice at rest, at the 3rd and 6th min of exercise, and every 5 min during the 20-min recovery. No significant effects of PEEP in resting pulmonary function values was found nor was PET CO2 altered for rest, exercise, or recovery for PEEP vs normal trials. For the normal exercise tests, post-exercise broncho-constriction was shown by at 30% to 50% decrease in FEV1.0, 30% to 40% drop in PEF, and a 45% to 65% decrease in maximal flow at 50% VC (MEF50), comparing post-exercise values to rest. PEEP during and PEEP post conditions significantly (P less than 0.01) decreased the severity of exercise-induced asthma (EIA) as PEFR and FEV1.0 values remained within 20% of rest levels and MEF50 within 30%. Since PET CO2 was not altered by the PEEP conditions, the airway response cannot be mediated through CO2 effect, It is known that PEEP does reduce air trapping, but since PEEP during work had a lasting effect into recovery this indicates that some additional mechanism may be involved.
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