EZH2-mediated upregulation of ROS1 oncogene promotes oral cancer metastasis.

Current anti-epidermal growth factor receptor (EGFR) therapy for oral cancer does not provide satisfactory efficacy due to drug resistance or reduced EGFR level. As an alternative candidate target for therapy, here we identified an oncogene, ROS1, as an important driver for oral squamous cell carcinoma (OSCC) metastasis. Among tumors from 188 oral cancer patients, upregulated ROS1 expression strongly correlated with metastasis to lung and lymph nodes. Mechanistic studies uncover that the activated ROS1 results from highly expressed ROS1 gene instead of gene rearrangement, a phenomenon distinct from other cancers. Our data further reveal a novel mechanism that reduced histone methyltransferase EZH2 leads to a lower trimethylation of histone H3 lysine 27 suppressive modification, relaxes chromatin, and promotes the accessibility of the transcription factor STAT1 to the enhancer and the intron regions of ROS1 target genes, CXCL1 and GLI1, for upregulating their expressions. Down-regulation of ROS1 in highly invasive OSCC cells, nevertheless, reduces cell proliferation and inhibits metastasis to lung in the tail-vein injection and the oral cavity xenograft models. Our findings highlight ROS1 as a candidate biomarker and therapeutic target for OSCC. Finally, we demonstrate that co-targeting of ROS1 and EGFR could potentially offer an effective oral cancer therapy.

Next Generation Driver for Attosecond and Laser-plasma Physics.

The observation and manipulation of electron dynamics in matter call for attosecond light pulses, routinely available from high-order harmonic generation driven by few-femtosecond lasers. However, the energy limitation of these lasers supports only weak sources and correspondingly linear attosecond studies. Here we report on an optical parametric synthesizer designed for nonlinear attosecond optics and relativistic laser-plasma physics. This synthesizer uniquely combines ultra-relativistic focused intensities of about 1020 W/cm2 with a pulse duration of sub-two carrier-wave cycles. The coherent combination of two sequentially amplified and complementary spectral ranges yields sub-5-fs pulses with multi-TW peak power. The application of this source allows the generation of a broad spectral continuum at 100-eV photon energy in gases as well as high-order harmonics in relativistic plasmas. Unprecedented spatio-temporal confinement of light now permits the investigation of electric-field-driven electron phenomena in the relativistic regime and ultimately the rise of next-generation intense isolated attosecond sources.

Noninvasive tongue-motion controlled computer mouse for the disabled.

BACKGROUND: A patient whose spinal cord was damaged due to accident may result in Tetraplegia or lose the ability to control his/her daily living environment. Currently, patients must use an invasive tool tongue movement, to help the patient communicate with the external environment. OBJECTIVE: This study designed a non-invasive tongue movement computer mouse system that allows the patient to use tongue movement to control a computer to communicate with the external environment. METHODS: Via a pressure sensor and assistive holder designed in this study, the pressure sensor can be moved using the assistive holder close to the mylohyoid muscle of the patient's lower jaw. The changes in pressure from the mylohyoid muscle are converted into computer mouse control signals to control a computer to communicate with the external environment. RESULTS: This study is based on ISO9241-Part 9 to design four kinds of training modes with varying difficulties. The data were collected from five able persons participating in the test over 7 days. The data includes throughput, path efficiency, test completion time and reaction time. The data verifies that the proposed system is stable and practical for persons with disabilities. CONCLUSION: The non-invasive computer mouse system for sensing tongue movement can completely breakthrough the limitations of the invasive tongue movement sensing system. This study uses non-invasive, simple tongue movements that correspond to the stretching and shrinking of the lower jaw mylohyoid muscle to control the computer mouse.

Electron Rephasing in a Laser-Wakefield Accelerator.

An important limit for energy gain in laser-plasma wakefield accelerators is the dephasing length, after which the electron beam reaches the decelerating region of the wakefield and starts to decelerate. Here, we propose to manipulate the phase of the electron beam in the wakefield, in order to bring the beam back into the accelerating region, hence increasing the final beam energy. This rephasing is operated by placing an upward density step in the beam path. In a first experiment, we demonstrate the principle of this technique using a large energy spread electron beam. Then, we show that it can be used to increase the energy of monoenergetic electron beams by more than 50%.

Effects of swimming on eye hand coordination and balance in the elderly.

OBJECTIVE: To evaluate the effects of swimming on upper extremity motor control, and balance in elderly population. DESIGN: Cross-sectional study. SETTING: The biomechanical laboratory in a tertiary hospital. PARTICIPANTS: The swimming group consisted of 20 swimmers (n_20, 65.4 ± 5.5 years) who received regular swimming exercise for more than 2 years. The control group consisted of 34 healthy active subjects (n_34, 67.4 ± 5.7 years) who have regular exercises other than swimming. MEASUREMENTS: The eye hand coordination was evaluated by calculating the mean reaction time required in accurately pointing onto the center of the target sensors that come in three different sizes (1 cm, 1.5 cm, and 2 cm in diameter). The SMART Balance Master device was used to measure posture balance. The maximal stability, center of pressure (COP) velocity, and percentage ankle strategy were obtained under six different balance conditions. RESULTS: In the testing of upper extremity motor control, the swimming group had significant shorter mean reaction time as compared with the control group in all three target sensor sizes (p < 0.05). In balance testing, the swimming group had significant greater percentage of ankle strategy during eyes closed and fixed support (EC), and sway-referenced vision and support (SVSS) conditions as compared with the control group (p < 0.05). CONCLUSION: Regular swimming exercise may result in improved eye hand coordination as faster and more accurate repetitive movements. Swimming may also result in improved balance function under few complicated balance conditions.

Vastus medialis obliquus and vastus lateralis activity in open and closed kinetic chain exercises in patients with patellofemoral pain syndrome: an electromyographic study.

OBJECTIVES: To evaluate the electromyographic activities of vastus medialis obliquus (VMO) and vastus lateralis (VL) muscles in open and closed kinetic chain exercises in subjects with patellofemoral pain syndrome (PFPS). DESIGN: Case-controlled study. SETTING: Rehabilitation science center in a tertiary medical center. PARTICIPANTS: Ten patients with bilateral knee pain diagnosed with PFPS and 10 healthy volunteers. INTERVENTIONS: Subjects performed open kinetic chain exercise on an isokinetic dynamometer and closed kinetic chain exercise by squat-to-stand and stand-to-squat tasks. Surface electromyography was done for the VMO and VL muscles. MAIN OUTCOME MEASURES: VMO/VL ratios were calculated after normalization of muscle activities. RESULTS: The VMO/VL ratios of PFPS subjects were significantly lower than were those of unimpaired subjects during knee isokinetic closed kinetic chain exercises (p = .047). However, there was no statistical difference in VMO/VL ratio between subjects with and without PFPS during closed kinetic chain exercises (p = .623). Maximum VMO/VL ratio was obtained at 60 degrees knee flexion in closed kinetic chain exercise. CONCLUSION: In closed kinetic chain exercises, more selective VMO activation can be obtained at 60 degrees knee flexion. Maximal VMO/VL ratio was observed at this knee flexion angle, and muscle contraction intensity was also greatest.

Coordination exercise and postural stability in elderly people: Effect of Tai Chi Chuan.

OBJECTIVE: To evaluate the effects of coordination exercise on postural stability in older individuals by Chinese shadow boxing, Tai Chi Chuan (TCC). DESIGN: Cross-sectional study. SETTING: Research project in a hospital-based biomechanical laboratory. PARTICIPANTS: The TCC group (n = 25) had been practicing TCC regularly for 2 to 35 years. The control group (n = 14) included healthy and active older subjects. INTERVENTION: Static postural stability test: progressively harder sequential tests with 6 combinations of vision (eyes open, eyes closed, sway-referenced) and support (fixed, sway-referenced); and dynamic balance test: 3 tests of weight shifting (left to right, forward-backward, multidirectional) at 3 speeds. MAIN OUTCOME MEASURES: Static and dynamic balance of Sensory Organization Testing (SOT) of the Smart Balance Master System. RESULTS: In static postural control, the results showed no differences between the TCC or control group in the more simple conditions, but in the more complicated SOT (eyes closed with sway surface, sway vision with sway surface), the TCC group had significantly better results than the control group. The TCC group also had significantly better results in the rhythmic forward-backward weight-shifting test. Duration of practice did not seem to affect the stability of elder people. CONCLUSION: The elderly people who regularly practiced TCC showed better postural stability in the more challenged conditions than those who do not (eg, the condition with simultaneous disturbance of vision and proprioception). TCC as a coordination exercise may reduce the risk of a fall through maintaining the ability of posture control.

Cytomegalovirus drug resistance and clinical implications.

Antiviral agents are commonly used for cytomegalovirus (CMV) prophylaxis or therapy after solid organ transplantation. Until recently, the detection of drug-resistant CMV in this setting was rare, but ganciclovir resistance has now been reported to occur in 5-10% of high-risk patient subsets, such as those undergoing primary CMV infection. Persistent viral shedding or progressive CMV disease after several weeks of antiviral therapy may indicate a problem with drug resistance, though laboratory testing is required to confirm this. Rapid genotypic assays for specific mutations in the viral UL97 phosphotransferase or UL54 DNA polymerase genes can be used to detect resistance and predict cross-resistance to other drugs. The emergence of drug resistance may be reduced by optimization of host immunity, use of potent antiviral drug regimens, and adherence to dosing regimens that adequately suppress viral replication.

Motor control assessment for rhizotomy in cerebral palsy.

OBJECTIVE: To apply motor control assessment for selection of appropriate spastic cerebral palsy children to receive selective posterior rhizotomy (SPR). DESIGN: Forty children with spastic cerebral palsy (3-16 yr) were divided into three groups: "independent ambulator," "dependent ambulator," and "nonambulator." Another 18 healthy children were selected as the control group. Both motor control (tested by using polyelectromyography (PEMG)) and clinical ambulatory capability were assessed within 1 mo before SPR and 12 mo after. PEMG patterns were classified into seven patterns according to electromyographic activities during hip/knee flexion and extension. Gait patterns, which were analyzed by computer DynoGraphy, were classified into four patterns for children with ambulatory capability. RESULTS: PEMG and gait patterns were correlated with ambulatory ability. PEMG patterns 2-3 could predict independent ambulatory ability, whereas patterns 6-7 will interfere with ambulatory ability. PEMG patterns showed significant improvement after SPR in the ambulatory groups (P < 0.05), whereas they did not improve in the nonambulator group. Children with cerebral palsy with co-contraction of proximal/distal muscles had better results after SPR, whereas those with diffuse co-contraction or reduced electromyography activities had poor results. CONCLUSIONS: PEMG patterns may allow the physician to select the appropriate children with spastic cerebral palsy to receive SPR with good results.

The effect of ankle joint position and effort on quadriceps reflex sensitivity.

OBJECTIVE: To investigate a possible ankle-knee synergy, experiments with normal subjects were performed to compare changes of the quadriceps motor pool excitability due to ankle position and effort. METHODS: Vastus medialis H reflex amplitude was examined during ankle isometric contractions conditioned by different ankle positions (dorsiflexion, neutral, and plantarfiexion) with or without voluntary effort (either in the dorsiflexion or plantarflexion direction). Repeated measures ANOVAs were performed on the mean and standard deviation of the H peak-to-peak amplitude. RESULTS: Mean vastus medialis H reflex amplitudes were significantly different among the trials of different ankle efforts (P<0.05), and significantly increased during plantarfiexion efforts. In contrast, mean vastus medialis H reflex amplitude did not vary with respect to changes of ankle position (P>0.05). CONCLUSIONS: The data suggest that (1) the position of the ankle joint did not significantly modify the excitability of the neuromotor pool of the VM muscle, in either static or active cases, and (2) the effort effect from the ankle joint on the VM neuromotor pool is most significant during ankle plantarfiexion effort. Possible mechanisms are central motor irradiation and peripheral force-dependent pathways from the ankle joint that influence the VM neuromotor pool.

The effects of Tai Chi Chuan on postural stability in the elderly: preliminary report.

BACKGROUND: Tai chi chuan (TCC) is a traditional Chinese conditioning exercise, consisting of a series of graceful movements linked together in a continuous sequence so that the body is constantly shifting from one foot to the other. We propose that subjects practicing TCC will have better postural control and stability than will active non-practitioners. METHODS: We compare static and dynamic postural controls in 14 TCC practitioners and 14 healthy active older adults using the Smart Balance Master System. The TCC group, containing 7 male and 7 female subjects (mean age, 70.9 +/- 3.3 years), had been practicing TCC regularly for 2 to 35 years. The control group included 4 male and 10 female healthy and active older subjects (mean age, 69.1 +/- 3.1 years), with age and body size matched to the TCC group. RESULTS: The results of static postural control tests showed no differences between the TCC and control groups under simple conditions (eyes open, eyes closed, swaying vision, and eyes open with swaying surface), but in the more complicated conditions (eyes closed with sway-referenced support and sway-referenced vision and support), the TCC group had significantly better results than the control group. In the dynamic balance test, the TCC group had significantly better results only in the rhythmic forward-backward weight-shifting test. CONCLUSION: Our data demonstrate that regular TCC practitioners have better postural stability, especially in the more complicated conditions with disturbed visual and somatosensory conditions.

Microbial dechlorination of polychlorinated biphenyls in anaerobic sewage sludge.

The potential of a chlorophenol (CP)-adapted consortium to dechlorinate polychlorinated biphenyls (PCBs) in sewage sludge was investigated. Results show that dechlorination rates differed significantly depending on sludge source and PCB congener. Higher total solid concentrations in sewage sludge and higher concentrations of chlorine in PCB resulted in slower dechlorination rates. No significant difference was found for 2,3,4,5-CB dechlorination from pH 6.0 to pH 8.0; however, dechlorination did not occur at pH 9.0 during a 41-day incubation period. Results show that at concentrations of 1 to 10 mg/L, the higher the PCB concentration, the faster the dechlorination rate. In addition, dechlorination rates were in the following order: methanogenic conditions > sulfate-reducing conditions > denitrifying conditions. The addition of acetate, lactate, pyruvate, and ferric chloride decreased lag times and enhanced dechlorination; however, the addition of manganese dioxide had an inhibitory effect. Dechlorination rates were also enhanced by the addition of PCB congeners, including 2,3,4-CB, 2,3,4,5-CB and 2,3,4,5,6-CB in mixture. Overall results show that the CP-adapted consortium has the potential to enhance PCB dechlorination. The optimal dechlorination conditions presented in this paper may be used as a reference for feasibility studies of PCB removal from sludge.

Cytomegalovirus-induced regulation of major histocompatibility complex class I antigen expression in human aortic smooth muscle cells.

Cardiac allograft vasculopathy (accelerated transplant atherosclerosis) is considered by most to involve a chronic allogeneic immune response to one or more constituents in the coronary vascular wall. Recent evidence suggests that there is an association between cytomegalovirus infection and the development of cardiac allograft vasculopathy (CAV). To determine whether CMV directly infects and/or potentially influences immunogenicity of vascular tissue, human umbilical vein (HU-VECs) or human aortic (HAECs) endothelial cells and human aortic smooth muscle cells (HASMCs) were isolated, cultured, and infected with CMV strain AD 169. Infection was detected using an immunoperoxidase-labeled monoclonal antibody to CMV immediate-early antigen (L-14). The presence and relative quantity of MHC class I and II antigens were determined flow cytometrically using monoclonal antibodies to monomorphic class I and class II HLA determinants. Gamma interferon was used as a positive control stimulant for the upregulation of MHC determinants. Both pooled HUVECs as well as 2 cell lines of HAECs served as targets for CMV infection though less than 10% of the cells were infected despite inocula of 10 pfu/cell. Infection of the pooled HUVECs resulted in no significant changes in the cell surface density of either MHC class I or II determinants. In contrast, HASMCs were excellent targets for CMV infection with virtually 100% of cells infected. CMV infection of 2 distinct HASMC cultures resulted in an increase of 254 +/- 158 relative fluorescence units (RFUs) in MHC class I antigen expression, as assessed by fluorescence intensity, in a variable portion of the HASMCs. A second population of cells exhibited a decrease of 73 +/- 16 RFUs in MHC class I antigen expression. No significant change in MHC class II antigen expression was noted. These results demonstrate that while HUVECs and HAECs are targets of CMV infection, human aortic smooth muscle cells can more readily be infected by CMV. Furthermore, CMV can regulate smooth muscle cell MHC class I expression, hence potentially altering immunogenicity. A pathophysiologic link between cardiac allograft vasculopathy and CMV disease can therefore be hypothesized.

Analysis of interstrain variation in cytomegalovirus glycoprotein B sequences encoding neutralization-related epitopes.

Nucleotide sequences of a part of the envelope glycoprotein B (gB) gene of human cytomegalovirus (CMV), encoding epitopes recognized by virus-neutralizing monoclonal antibodies, were determined for 12 distinct clinical strains of CMV after amplification of suitable templates using the polymerase chain reaction. Sequence analysis of this region (codons 384-717) revealed that the clinical strains and previously sequenced laboratory strains Towne and AD169 belong to one of four variant groups, each with a characteristic nucleotide and peptide sequence. Peptide homology was greater than 99% for strains within a group, and varied from 91% to 98% for strains in different groups. Variation was most frequent between codons 448 and 480. The gB group of a CMV strain could be determined by restriction analysis of a small target sequence amplified from viral genomic DNA, and an additional 28 clinical strains were grouped in this manner. The existence of a limited number of variants of gB among clinical strains facilitates analysis of biologic function and cross-reactivity of immune responses.

Differentiation of cytomegalovirus strains by restriction analysis of DNA sequences amplified from clinical specimens.

DNA sequences of 2.0 to 2.7 kb were amplified by polymerase chain reaction from four genes (major immediate-early, DNA polymerase, and glycoproteins B and H) of 20 distinct strains of cytomegalovirus (CMV). Analysis of the unpurified reaction products using selected restriction enzymes showed sufficient diversity of profiles among strains to differentiate all 20. Sequences suitable for restriction analysis were also amplified directly from clinical urine specimens and showed restriction profiles comparable to those of sequences amplified from corresponding CMV culture isolates. Ability to identify specific strains of CMV in amplification products facilitates molecular epidemiologic studies.

Rises in antibody to human herpesvirus 6 detected by enzyme immunoassay in transplant recipients with primary cytomegalovirus infection.

Immunoglobulin G to human herpesvirus 6 (HHV-6) and cytomegalovirus (CMV) in sera from solid organ recipients was measured by an enzyme-linked immunoassay (ELISA) before and after transplant. The HHV-6 ELISA was developed from glycine extracts of HHV-6-infected and uninfected HSB-2 cells. At a serum dilution of 1:500, 80 (91%) of 88 recipients were seropositive for HHV-6 before transplant, while only 14 (16%) were seropositive for CMV. Posttransplant HHV-6 serologic rises were observed in 38 (43%) recipients; rises in 25 of these recipients were associated with primary CMV infection. Titration of sera revealed much higher HHV-6 titer rises among those with primary CMV infection than among those with CMV reactivation or with no CMV infection. Elevated HHV-6 antibody titers persisted for up to 2 years after primary CMV infection. No correlation was noted between CMV and HHV-6 antibody titers in individual serum samples.

Reactivation and recombination of multiple cytomegalovirus strains from individual organ donors.

Close examination of restriction enzyme digest profiles of cytomegalovirus (CMV) isolates from corecipients of organs from a common donor revealed instances of intermittent or prolonged shedding of two strains transmitted from the same donor organ. In two corecipients, two distinct donor strains were isolated by end-point dilutions of urine specimens or of cell-free virus stock and were shown by monoclonal antibody staining to differ in their major immediate-early antigen. The separated strains retained stable restriction profiles through greater than 20 passages in cell culture. However, similar passage of the original mixed-strain clinical isolates gave rise to new, recombinant strains of CMV. These findings indicate that more than one strain of CMV can establish latency in normal hosts and suggest that new viral strains arise readily through recombination of existing strains.

Neutralizing antibody responses to reinfecting strains of cytomegalovirus in transplant recipients.

Analysis of cytomegalovirus (CMV) isolates shed by 51 recipients of organs from 24 CMV-seropositive donors was used to assess the relative characteristics of primary infection, reactivation of endogenous virus, and reinfection by a donor CMV strain. Reinfection was more frequent than reactivation of endogenous virus. Symptomatic CMV disease was identified in 21 of 25 primary infections, 2 of 16 reinfections, and 1 of 4 cases of endogenous reactivation. Before receiving a transplant, reinfected recipients had detectable neutralizing antibody to the specific reinfecting strain of CMV and to laboratory strain AD169. Following reinfection, rises in neutralizing antibody titers were observed, comparable to the responses of those with reactivation of endogenous CMV. The preexisting level of neutralizing antibody did not appear to predict clinical outcome, and moderately high levels of neutralizing antibody did not prevent viremia. Thus, posttransplant CMV reinfection occurs frequently and appears clinically, serologically, and virologically similar to reactivation of endogenous virus.

Latex agglutination and enzyme-linked immunosorbent assays for cytomegalovirus serologic screening of transplant donors and recipients.

The effectiveness of three serologic assays (two enzyme-linked immunosorbent assays [ELISAs] and latex agglutination) for cytomegalovirus (CMV) serologic matching of donors and recipients was assessed over a 2-year period in a major organ transplant program. Sera with equivocal test results were investigated by repeat testing of serum samples and additional specimens from the individuals involved and monitoring of CMV infection in recipients. An in-house ELISA identified all CMV-infective donors as seropositive. Of 63 ELISA-positive donors, 5 were negative by latex agglutination; recipients from 3 of these donors developed primary CMV infection posttransplant. The in-house ELISA and a commercial ELISA (Abbott enzyme immunoassay; Abbott Laboratories, North Chicago, Ill.) had a 93% concordance of results; follow-up testing indicated that the Abbott assay was sensitive but had a false-positive rate of about 11%. One recipient with a false-positive result developed symptomatic primary CMV infection after receiving a seropositive organ. Thus, performance characteristics of currently used screening assays affect recipient outcome.