Citations

Abstract Barrett's esophagus, a columnar metaplasia of the lower esophagus epithelium related to gastroesophageal reflux disease, is the strongest known risk factor for the development of esophageal adenocarcinoma (EAC). Understanding the signal transduction events involved in esophageal epithelium carcinogenesis may provide insights into the origins of EAC and may suggest new therapies. To elucidate the molecular pathways of bile acid–induced tumorigenesis, the newly identified inflammation-associated signaling pathway involving IκB kinases β (IKKβ), tuberous sclerosis complex 1 (TSC1), and mammalian target of rapamycin (mTOR) downstream effector S6 kinase (S6K1) was confirmed to be activated in immortalized Barrett's CPC-A and CPC-C cells and esophageal cancer SEG-1 and BE3 cells. Phosphorylation of TSC1 and S6K1 was induced in response to bile acid stimulation. Treatment of these cells with the mTOR inhibitor rapamycin or the IKKβ inhibitor Bay 11-7082 suppressed bile acid–induced cell proliferation and anchorage-independent growth. We next used an orthotopic rat model to evaluate the role of bile acid in the progression of Barrett's esophagus to EAC. Of interest, we found high expression of phosphorylated IKKβ (pIKKβ) and phosphorylated S6K1 (pS6K1) in tumor tissues and the Barrett's epithelium compared with normal epithelium. Furthermore, immunostaining of clinical EAC tissue specimens revealed that pIKKβ expression was strongly correlated with pS6K1 level. Together, these results show that bile acid can deregulate TSC1/mTOR through IKKβ signaling, which may play a critical role in EAC progression. In addition, Bay 11-7082 and rapamycin may potentially be chemopreventive drugs against Barrett's esophagus–associated EAC. [Cancer Res 2008;68(8):2632–40]

Background Percutaneous coronary revascularization (PCI) has been increasingly applied to unprotected left main trunk (LMT) lesions, with varied long-term success. This study attempts to define the predictors of outcome in this population. Methods and Results Two hundred seventy-nine consecutive patients who had LMT PCI at 1 of 25 sites between 1993 and 1998 were studied. Forty-six percent of these patients were deemed inoperable or at high surgical risk. Thirty-eight patients (13.7%) died in hospital, and the rest were followed up for a mean of 19 months. The 1-year incidence was 24.2% for all-cause mortality, 20.2% for cardiac mortality, 9.8% for myocardial infarction, and 9.4% for CABG. Independent correlates of all-cause mortality were left ventricular ejection fraction ≤30%, mitral regurgitation grade 3 or 4, presentation with myocardial infarction and shock, creatinine ≥2.0 mg/dL, and severe lesion calcification. For the 32% of patients <65 years old with left ventricular ejection fraction >30% and without shock, the prevalence of these adverse risk factors was low. No periprocedural deaths were observed in this low-risk subset, and the 1-year mortality was only 3.4%. Conclusions Patients undergoing unprotected LMT PCI have frequent serious comorbidities and consequently have high event rates. PCI may be an alternative to CABG for a select proportion of elective patients and may also be appropriate for highly symptomatic inoperable patients. Meticulous follow-up of hospital survivors is required because of the rather high mortality during the first few months after treatment.

Despite the use of wrist guards during skate- and snowboard activities, fractures still occur at the wrist or at further proximal locations of the forearm. The main objectives of this study were to conduct a human subject testing under simulated falling conditions for measurement of the impact force on the hand, to model wrist guards as a shock isolator, to construct a linear mass-spring-damper model for quantification of the impact force attenuation (Q-ratio) and energy absorption (S-ratio), and to determine whether wrist guards play a role of an efficient shock isolator. While the falling direction (forward and backward) significantly influenced the impact responses, use of wrist guards provided minimal improvements in the Q- and S-ratios. It was suggested based on the results under the submaximal loading conditions that protective functions of the common wrist guard design could be enhanced with substantial increase in the damping ratio so as to maximize the energy absorption. This would bring forth minor deterioration in the impact force attenuation but significant increase in the energy absorption by 19%, which would help better protection against fall-related injuries of the upper extremity.

The purpose of this study is to develop an electromechanical system for dynamic simulation of the stance phase of a human gait using cadaveric foot specimens. The system can be used for quantification of foot and ankle pathomechanics and design of foot and ankle reconstructive surgeries. Servo-pneumatic systems were used for application of the tibial weight loading and muscle loadings. A four-bar mechanism was constructed to provide the progressive motion of a tibia during the simulation while the external loadings were simultaneously applied. Muscle loadings were estimated based on the physiological cross-sectional area and normal electromyography (EMG) data with the assumption of the linear EMG–force relationship. Ad hoc tuning of the unknown muscle gains was conducted until a reasonable match with the normal vertical ground reaction force profile, center of pressure advancement, and characteristic foot motion events (heel strike, foot flat, heel rise and toe-off) could be made. Three cadaver feet and an artificial foot were tested with five repeated trials. The simulator reproduced the stance phase of a human gait in the sagittal plane with reasonable accuracy and consistency without compromising either kinematics or kinetics of the foot and ankle complex.

ABSTRACTOn viral infection, infected cells can become the target of host immune responses or can go through a programmed cell death process, called apoptosis, as a defense mechanism to limit the ability of the virus to replicate. To prevent this, viruses have evolved elaborate mechanisms to subvert the apoptotic process. Here, we report the identification of a novel antiapoptotic K7 protein of Kaposi's sarcoma-associated herpesvirus (KSHV) which expresses during lytic replication. The KSHV K7 gene encodes a small mitochondrial membrane protein, and its expression efficiently inhibits apoptosis induced by a variety of apoptogenic agents. The yeast two-hybrid screen has demonstrated that K7 targets cellular calcium-modulating cyclophilin ligand (CAML), a protein that regulates the intracellular Ca2+concentration. Similar to CAML, K7 expression significantly enhances the kinetics and amplitudes of the increase in intracellular Ca2+concentration on apoptotic stimulus. Mutational analysis showed that K7 interaction with CAML is required for its function in the inhibition of apoptosis. This indicates that K7 targets cellular CAML to increase the cytosolic Ca2+response, which consequently protects cells from mitochondrial damage and apoptosis. This is a novel viral antiapoptosis strategy where the KSHV mitochondrial K7 protein targets a cellular Ca2+-modulating protein to confer resistance to apoptosis, which allows completion of the viral lytic replication and, eventually, maintenance of persistent infection in infected host.