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Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) is expressed in the epithelial cells of a wide range of organs/tissues from which most cancers are derived. Although accumulating reports have indicated the association of cancer incidence with genetic variations in CFTR gene, the exact role of CFTR in cancer development and the possible underlying mechanism have not been elucidated. Here, we report that CFTR expression is significantly decreased in both prostate cancer cell lines and human prostate cancer tissue samples. Overexpression of CFTR in prostate cancer cell lines suppresses tumor progression (cell growth, adhesion and migration), whereas knockdown of CFTR leads to enhanced malignancies both in vitro and in vivo. In addition, we demonstrate that CFTR knockdown-enhanced cell proliferation, cell invasion and migration are significantly reversed by antibodies against either urokinase plasminogen activator (uPA) or uPA receptor (uPAR), which are known to be involved in various malignant traits of cancer development. More interestingly, overexpression of CFTR suppresses uPA by upregulating the recently described tumor suppressor microRNA-193b (miR-193b), and overexpression of pre-miR-193b significantly reverses CFTR knockdown-enhanced malignant phenotype and abrogates elevated uPA activity in prostate cancer cell line. Finally, we show that CFTR gene transfer results in significant tumor repression in prostate cancer xenografts in vivo. Taken together, the present study has demonstrated a previously undefined tumor-suppressing role of CFTR and its involvement in regulation of miR-193b in prostate cancer development. [ABSTRACT FROM AUTHOR]

Minichromosome maintenance (MCM) proteins 2-7 are important in DNA replication licensing. Functional roles beyond licensing are speculated. In addition, significances in medulloblastoma (MB) remain unclear. In this study, we showed the frequent deregulation of MCM2 and MCM3 expression in 7 MB cell lines and 31 clinical samples. Moreover, DAOY and ONS76 and the clinical samples expressed elevated MCM7 transcripts with genomic gain of the gene. Immunopositivity restricted to tumor cells was found in 41, 37 and 53 out of 73 MB cases for MCM2, MCM3 and MCM7, respectively. High-MCM3 expression was associated with poor prognosis. Knockdowns of these MCMs significantly inhibited anchorage-dependent and -independent MB cell growth. The inhibition of MCM3 expression by small interfering RNA knockdown was related to G1 arrest with reduced cyclin A expression, whereas the MCM2- and MCM7-knocked-down cells arrested at G2/M with increased cyclin A expression. Interestingly, we demonstrated the links of these MCMs with cell migration and invasion using wound-healing and Transwell migration/invasion assays. Exogenous overexpression of MCM2, MCM3 and MCM7 increased anchorage-independent cell growth, and also cell migration and invasion capabilities in MB cells. The knockdown reduced the number of filopodial cells and the cells with intense stress fibers by blocking cdc42 and Rho activation. Taken together, deregulation of MCM2, MCM3 and MCM7 expression might be involved in MB tumorigenesis and we revealed undefined roles of these MCMs in control of MB cell migration and invasion. [ABSTRACT FROM AUTHOR]

G-protein-coupled receptor-30 (GPR30) shows estrogen-binding affinity and mediates non-genomic signaling of estrogen to regulate cell growth. We here showed for the first time, in contrast to the reported promoting action of GPR30 on the growth of breast and ovarian cancer cells, that activation of GPR30 by the receptor-specific, non-estrogenic ligand G-1 inhibited the growth of androgen-dependent and androgen-independent prostate cancer (PCa) cells in vitro and PC-3 xenografts in vivo. However, G-1 elicited no growth or histological changes in the prostates of intact mice and did not inhibit growth in quiescent BPH-1, an immortalized benign prostatic epithelial cell line. Treatment of PC-3 cells with G-1 induced cell-cycle arrest at the G2 phase and reduced the expression of G2-checkpoint regulators (cyclin-A2, cyclin-B1, cdc25c, and cdc2) and phosphorylation of their common transcriptional regulator NF-YA in PC-3 cells. With extensive use of siRNA-knockdown experiments and the MEK inhibitor PD98059 in this study, we dissected the mechanism underlying G-1-induced inhibition of PC-3 cell growth, which was mediated through GPR30, followed by sustained activation of Erk1/2 and a c-jun/c-fos-dependent upregulation of p21, resulting in the arrest of PC-3 growth at the G2 phase. The discovery of this signaling pathway lays the foundation for future development of GPR30-based therapies for PCa. [ABSTRACT FROM AUTHOR]

Nasopharyngeal carcinoma (NPC) is an Epstein–Barr virus-associated disease with high prevalence in Southern Chinese. Using multiparametric flow cytometry, we identified significant expansions of circulating naïve and memory CD4+CD25high T cells in 56 NPC patients compared with healthy age- and sex-matched controls. These were regulatory T cells (Treg), as they overexpressed Foxp3 and GITR, and demonstrated enhanced suppressive activities against autologous CD4+CD25− T-cell proliferation in functional studies on five patients. Abundant intraepithelial infiltrations of Treg with very high levels of Foxp3 expression and absence of CCR7 expression were also detected in five primary tumours. Our current study is the first to demonstrate an expansion of functional Treg in the circulation of NPC patients and the presence of infiltrating Treg in the tumour microenvironment. As Treg may play an important role in suppressing antitumour immunity, our findings provide critical insights for clinical management of NPC.British Journal of Cancer (2007) 96, 617–622. doi:10.1038/sj.bjc.6603580 www.bjcancer.com Published online 30 January 2007 [ABSTRACT FROM AUTHOR]

We performed a retrospective analysis on the human leukocyte antigen (HLA) data of 53 consecutive Chinese patients with high-risk childhood acute lymphoblastic leukemia (ALL) diagnosed from 1989 to 2003. A significantly higher frequency of HLA-B67 in the male relapse group of patients [OR, 23.08; 95% CI, 5.31–100.36; p=0.0042; for statistical significance after Bonferroni correction (Bc) p Bc<0.0083] was identified after Bonferroni correction. Although not surviving the Bonferroni correction, gender effects on the association were also observed with HLA-A11, HLA-A32, HLA-A33, and HLA-B22, which were however more prevalent in the female patients and particularly those developing relapse. Two patients with HLA-A29 and HLA-B7 revealed significantly shortened survivals, suggestive of their potential prognostic impacts. Notably, for the first time, we found a significant correlation of leukocyte count with HLA types, where HLA-A33 ( p=0.006) or HLA-B17 ( p<0.001) signifies higher leukocytosis at presentation. Taken together, our findings support the involvement of HLA in Chinese high-risk childhood ALL. [ABSTRACT FROM AUTHOR]

In this paper we present results of a numerical study using the NASA finite-volume GCM to elucidate a plausible mechanism for aerosol impact on the Asian summer monsoon involving interaction with physical processes over the Tibetan Plateau (TP). During the pre-monsoon season of March–April, dusts from the deserts of western China, Afghanistan/Pakistan, and the Middle East are transported into and stacked up against the northern and southern slopes of the TP. The absorption of solar radiation by dust heats up the elevated surface air over the slopes. On the southern slopes, the atmospheric heating is reinforced by black carbon from local emission. The heated air rises via dry convection, creating a positive temperature anomaly in the mid-to-upper troposphere over the TP relative to the region to the south. In May through early June in a manner akin to an “elevated heat pump”, the rising hot air forced by the increasing heating in the upper troposphere, draws in warm and moist air over the Indian subcontinent, setting the stage for the onset of the South Asia summer monsoon. Our results suggest that increased dust loading coupled with black carbon emission from local sources in northern India during late spring may lead to an advance of the rainy periods and subsequently an intensification of the Indian summer monsoon. The enhanced rainfall over India is associated with the development of an aerosol-induced large-scale sea level pressure anomaly pattern, which causes the East Asia ( Mei-yu) rain belt to shift northwestward, suppressing rainfall over East Asia and the adjacent oceanic regions. [ABSTRACT FROM AUTHOR]

In this study, we perform experiments with a coupled atmosphere-ocean general circulation model (CGCM) to examine ENSO’s influence on the interannual sea-surface temperature (SST) variability of the tropical Indian Ocean. The control experiment includes both the Indian and Pacific Oceans in the ocean model component of the CGCM (the Indo-Pacific Run). The anomaly experiment excludes ENSO’s influence by including only the Indian Ocean while prescribing monthly-varying climatological SSTs for the Pacific Ocean (the Indian-Ocean Run). In the Indo-Pacific Run, an oscillatory mode of the Indian Ocean SST variability is identified by a multi-channel singular spectral analysis (MSSA). The oscillatory mode comprises two patterns that can be identified with the Indian Ocean Zonal Mode (IOZM) and a basin-wide warming/cooling mode respectively. In the model, the IOZM peaks about 3–5 months after ENSO reaches its maximum intensity. The basin mode peaks 8 months after the IOZM. The timing and associated SST patterns suggests that the IOZM is related to ENSO, and the basin-wide warming/cooling develops as a result of the decay of the IOZM spreading SST anomalies from western Indian Ocean to the eastern Indian Ocean. In contrast, in the Indian-Ocean Run, no oscillatory modes can be identified by the MSSA, even though the Indian Ocean SST variability is characterized by east–west SST contrast patterns similar to the IOZM. In both control and anomaly runs, IOZM-like SST variability appears to be associated with forcings from fluctuations of the Indian monsoon. Our modeling results suggest that the oscillatory feature of the IOZM is primarily forced by ENSO. [ABSTRACT FROM AUTHOR]

Prognostic cloud schemes are increasingly used in weather and climate models in order to better treat cloud-radiation processes. Simplifications are often made in such schemes for computational efficiency, like the scheme being used in the National Centers for Environment Prediction models that excludes some microphysical processes and precipitation-radiation interaction. In this study, sensitivity tests with a 2-D cloud resolving model are carried out to examine effects of the excluded microphysical processes and precipitation-radiation interaction on tropical thermodynamics and cloud properties. The model is integrated for 10 days with the imposed vertical velocity derived from the Tropical Ocean Global Atmosphere Coupled Ocean–Atmosphere Response Experiment. The experiment excluding the depositional growth of snow from cloud ice shows anomalous growth of cloud ice and more than 20% increase of fractional cloud cover, indicating that the lack of the depositional snow growth causes unrealistically large mixing ratio of cloud ice. The experiment excluding the precipitation-radiation interaction displays a significant cooling and drying bias. The analysis of heat and moisture budgets shows that the simulation without the interaction produces more stable upper troposphere and more unstable mid and lower troposphere than does the simulation with the interaction. Thus, the suppressed growth of ice clouds in upper troposphere and stronger radiative cooling in mid and lower troposphere are responsible for the cooling bias, and less evaporation of rain associated with the large-scale subsidence induces the drying in mid and lower troposphere. [ABSTRACT FROM AUTHOR]

The intraseasonal variability associated with the Asian summer monsoon as simulated by a number of atmospheric general circulation models (AGCMs) are analyzed and assessed against observations. The model data comes from the Monsoon GCM Intercomparison project initiated by the CLIVAR/Asian–Australian Monsoon Panel. Ten GCM groups, i.e., the Center for Ocean–Land–Atmosphere Studies (COLA), Institute of Numerical Mathematics (DNM), Goddard Space Flight Center (GSFC), Geophysical Fluid Dynamics Laboratory (GFDL), Institute of Atmospheric Physics (IAP), Indian Institute of Tropical Meteorology (IITM), Meteorological Research Institute (MRI), National Center for Atmospheric Research (NCAR), Seoul National University (SNU), and the State University of New York (SUNY), participated in the intraseasonal component of the project. Each performed a set of 10 ensemble simulations for 1 September 1996–31 August 1998 using the same observed weekly SST values but with different initial conditions. The focus is on the spatial and seasonal variations associated with intraseasonal variability (ISV) of rainfall, the structure of each model's principal mode of spatial-temporal variation of rainfall [i.e. their depiction of the Intraseasonal Oscillation (ISO)], the teleconnection patterns associated with each model's ISO, and the implications of the models' ISV on seasonal monsoon predictability. The results show that several of the models exhibit ISV levels at or above that found in observations with spatial patterns of ISV that resemble the observed pattern. This includes a number of rather detailed features, including the relative distribution of variability between ocean and land regions. In terms of the area-averaged variance, it is found that the fidelity of a model to represent NH summer versus winter ISV appears to be strongly linked. In addition, most models' ISO patterns do exhibit some form of northeastward propagation. However, the model ISO patterns are typically less coherent, lack sufficient eastward propagation, and have smaller zonal and meridional spatial scales than the observed patterns, and are often limited to one side or the other of the maritime continent. The most pervasive and problematic feature of the models' depiction of ISV and/or their ISO patterns is the overall lack of variability in the equatorial Indian Ocean. In some cases, this characteristic appears to result from some models forming double convergence zones about the equator rather than one region of strong convergence on the equator. This shortcoming results in a poor representation of the local rainfall pattern and also significantly influences the models' representations of the global-scale teleconnection patterns associated with the ISO. Finally, analysis of the model ensemble shows a positive relationship between the strength of a model's ISV of rainfall and its intra-ensemble variability of seasonal monsoon rainfall. The implications of this latter relation are discussed in the context of seasonal monsoon predictability. [ABSTRACT FROM AUTHOR]

We assesses the overall performance of state-of-the-art atmospheric GCMs in simulating the climatological variations of summer monsoon rainfall over the Asian-Western Pacific region and the systematic errors that are common to a group of GCMs. The GCM data utilized are obtained from 10 GCM groups participated in the CLIVAR/Monsoon GCM Intercomparison Project. The model composite shows that the overall spatial pattern of summer monsoon rainfall is similar to the observed, although the western Pacific rainfall is relatively weak. For the simulated precipitation over the western Pacific, the models can be classified into two categories. The first category of models simulates the precipitation more confined to the equatorial region and weaker precipitation in the subtropical western Pacific compared to the observed. The second category of models simulates large precipitation in the subtropical western Pacific but the region is shifted to the north by 5–10°. None of the models realistically reproduce the observed Mei-yu rain band in the region from the East China Sea to the mid Pacific. Most of the models produce a rain band along the continental side of East Asia. The climatological variations of simulated summer rainfall are examined in terms of their amplitude and their principal EOF modes. All models simulate larger amplitudes of the climatological seasonal variation of Indian summer monsoon than the observed, though most models simulate smaller amplitudes in the western Pacific. The ten model composite produces four leading EOF modes over the Asian-western Pacific region, which are remarkably similar to the observed counterparts. The first and second eigenmodes, respectively, represent the smoothed seasonal march of broad-scale monsoon and the onsets of the Indian and East Asian summer monsoon. The third and fourth modes relate to the climatological intraseasonal oscillation (CISO). In contrast to the model composite, several models fail to reproduce the first principal mode, and most models do not reproduce the observed modes higher than the second. The CISO of precipitation is also examined over the Indian monsoon and the East Asia-western Pacific monsoon regions separately. [ABSTRACT FROM AUTHOR]

We have performed experiments using an ocean model to study the sensitivity of tropical Pacific Ocean to variations in precipitation induced freshwater fluxes. Variations in these fluxes arise from natural causes on all time scales. In addition, estimates of these fluxes are uncertain because of differences among measurement techniques. The model used is a quasi-isopycnal model, covering the Pacific from 40 °S to 40 °N. The surface forcing is constructed from observed wind stress, evaporation, precipitation, and sea surface temperature (SST) fields. The heat flux is produced with an iterative technique so as to maintain the model close to the observed climatology, but with only a weak damping to that climatology. Climatological estimates of evaporation are combined with various estimates of precipitation to determine the net surface freshwater flux. Results indicate that increased freshwater input decreases salinity as expected, but increases temperatures in the upper ocean. Using the freshwater flux estimated from the Microwave Sounding Unit leads to a warming of up to 0.6 °C in the western Pacific over a case with zero net freshwater flux. SST is sensitive to the discrepancies among different precipitation observations, with root-mean-square differences in SST on the order of 0.2–0.3 °C. The change in SST is more pronounced in the eastern Pacific, with difference of over 1 °C found among the various precipitation products. Interannual variation in precipitation during El Niño events leads to increased warming. During the winter of 1982–83, freshwater flux accounts for about 0.4 °C (approximately 10–15% of the maximum warming) of the surface warming in the central-eastern Pacific. Thus, the error of SST caused by the discrepancies in precipitation products is more than half of the SST anomaly produced by the interannual variability of observed precipitation. Further experiments, in which freshwater flux anomalies are imposed in the western, central, and eastern Pacific, show that the influence of net freshwater flux is also spatially dependent. The imposition of freshwater flux in the far western Pacific leads to a trapping of salinity anomalies to the surface layers near the equator. An identical flux imposed in the central Pacific produces deeper and off-equatorial salinity anomalies. The contrast between these two simulations is consistent with other simulations of the western Pacific barrier layer formation. [ABSTRACT FROM AUTHOR]

The relative roles of internal atmospheric dynamics, land surface evaporation and sea surface temperature (SST) forcings on the coupling between the Asian monsoon (AM) and the Southern Oscillation (SO) are investigated in a series of GCM experiments. Results confirm previous studies indicating that the characteristic large-scale pattern of the SO is due primarily to SST anomaly (SSTA) forcing. The AM circulation anomalies are coupled to the SO via a characteristic upper level circulation couplet over the equatorial central Pacific. This couplet acts as a radiating node for teleconnection signals originating from the AM region to the extratropics. Generally, a weak AM is associated with warm SST over the eastern equatorial Pacific, concomitant with the negative phase of the SO, i.e., low (high) surface pressure over Tahiti (Darwin). The reverse holds for strong AM. Two wavetrains associated with the AM fluctuation have been identified: one arcing over northeastern Asia via the Aleutians to North American, and another emanating from northwestern Europe, via Siberia to northern India. Internal dynamics appear to underpin the origin of these wavetrains, which are strongly tempered by SSTA forcing and to a lesser degree by interactive land processes. Regionally, land-atmosphere interaction seems to have the strongest impact over East Asia/Indochina and the adjacent oceanic region of the South China Sea. Here, land-atmosphere interaction is responsible for the enhancement of a subseasonal scale see-saw oscillation in precipitation between land and the adjacent oceans. A local land-atmosphere feedback mechanism involving strong coupling between the hydrologic and energy cycles is identified. It is suggested that the interaction among precipitation, moisture convergence and land surface turbulent heat fluxes and radiation processes play key roles in determining the fast (subseasonal and shorter scales) response of the AM. On these time scales, the occurrences of cool/wet and hot/dry states associated with the precipitation seesaw appear to be chaotic. However, the preferred occurrence of a given state and the abrupt transition between states are dependent on the large-scale circulation and radiation forcings induced by the SO. One of the more provocative findings here is that effects of land-atmosphere interaction do not seem to alter the basic planetary scale features of the AM-SO system. As a result, the interannual variability of the coupled AM-SO is relatively small in the absence of anomalous SST forcing. Yet, the local effect of land-atmosphere interaction on AM is quite pronounced and dependent upon the large-scale forcings related to SO. [ABSTRACT FROM AUTHOR]

This study evaluates simulations of the East Asian winter monsoon in eight GCMs that participated in the Atmospheric Model Intercomparison Project (AMIP). In addition to validating the mean state of the winter monsoon, the cold surge and its transient properties, which includes the frequency, intensity, preferred propagation tracks, and the evolution patterns of the surges, are examined. GCM simulated temporal distribution of the Siberian high and cold surges is also discussed. Finally, the forcing of the cold surges on the tropical surface wind and convection, along with their interannual variation is analyzed. The mean state of the winter monsoon is generally portrayed well in most of the models. These include the climatological position of the Siberian high, the 200 hPa divergent center, and the large-scale wind patterns at the surface and the 200 hPa. Models display a wide range of skill in simulating the cold surge and its transient properties. In some of the models, the simulated cold surge trajectory, intensity, frequency, propagation patterns and source regions are in general agreement with those from the observed. While in others, the models cannot adequately capture these observed characteristics. The temporal distribution of the Siberian high and cold surges were realistically reproduced in most GCMs. Most models were able to simulate the effect of the cold surges on the tropical surface wind, although a few models unrealistically generated subtropical southerly wind in the mid-winter. The relationship between cold surges and the tropical convection was not satisfactorily simulated in most models. The common discrepancies in the winter monsoon simulation can be attributed to many factors. In some models, the reason is directly related to the improper location of the large-scale convective center near the western Pacific. The satisfactory simulations of the monsoon circulation and the cold surges are partly due to the topographical characteristics of the East Asian continent, i.e., the Tibetan Plateau to the west and the oceans to the east. The correct simulation of the interannual variation of the surface wind near the South China Sea (SCS) and the maritime continent is a demanding task for most of the models. This will require adequate simulations of many aspects, including tropical convection, the Siberian cold dome, the extratropical-tropical linkage, and the air-sea interaction. The discrepancies noted here furnish a guide for the continuing improvement of the winter monsoon simulations. Improved simulations will lead to an adequate delineation of the surface wind and convection near the maritime continent, which is essential for portraying the winter monsoon forcing in a coupled model. [ABSTRACT FROM AUTHOR]

The multi-scale time-space regimes of the low-frequency convective activity over the maritime continent and tropical western Pacific are investigated using the monthly infrared radiance black body temperature (IRTBB) over a latitude band of 5S--9S, 80E--16OW for the time period of 1980--1993. The complex Morlet wavelet transform and the complex empirical orthogonal function (CEOF) analysis are used. The zonal mean of the monthly IRTBB is dominated by the annual cycle which is influenced by a monsoon regime. An interannual signal around the time scale of 4.8-year and a decadal signal are obvious. In the zonal deviation, each CEOF represents a particular spatial regime; its corresponding principal component exhibits different multi-scale temporal behavior. The first leading component represents the variability due to large scale land-ocean distribution (the maritime continent, the Indian Ocean and the western Pacific) related to monsoon, with a dominantannual time scale. The second leading component represents the fluctuation of Walker circulation, associated with the El Nino-Southern Oscillation (ENSO) events having a main time scale around 4.8-year and the quasi-biennial oscillation (QBO) around 2.4-year. The third leading component represents the variability due to small-scale land--ocean distribution (Java, New Guinea and the surrounding seas), with a dominant annual time scale. The main time scales in all the components seem to be modulated by longer time scales in either amplitude or frequency or both. Different time scales, as well as their in-phase interference, may play different roles in developing an individual ENSO event. The 1982/1983 event is dominated by an enhanced QBO. The 1986/1987 event is dominated by an enhanced 4.8-year oscillation. The 1991 and 1993 events may have resulted from an in-phase interference amongseveral interannual time scales, abnormal annual cycles, and also high-frequency variability. [ABSTRACT FROM AUTHOR]