Farnesyltransferase Inhibitors Reduce Ras Activation and Ameliorate Acetaminophen-Induced Liver Injury in Mice

Hepatotoxicity due to overdose of the analgesic and antipyretic acetaminophen (A-PAIP) is a major cause of liver failure in adults. To better understand the contributions of different signaling pathways, the expression and role of Ras activation was evaluated after oral dosing of mice with APAP (400-500 mg/kg). Ras-guanosine triphosphate (GTP) is induced early and in an oxidative stress-dependent manner. The functional role of Ras activation was studied by a single intraperitoneal injection of the neutral sphingomyelinase and farnesyltransferase inhibitor (FTI) manumycin A (I mg/kg), which lowers induction of Ras-GTP and serum amounts of alanine aminotransferase (ALT). APAP dosing decreases hepatic glutathione amounts, which are not affected by manumycin A treatment. However, APAP-induced activation of c-Jun N-terminal kinase, which plays an important role, is reduced by manumycin A. Also, APAP-induced mitochondrial reactive oxygen species are reduced by manumycin A at a later time point during liver injury. Importantly, the induction of genes involved in the inflammatory response (including iNos, gp91phox, and Fasl) and serum amounts of proinflammatory cytokines interferon-gamma (IFN gamma) and tumor necrosis factor alpha, which increase greatly with APAP challenge, are suppressed with manumycin A. The FTI ctivity of manumycin A is most likely involved in reducing APAP-induced liver injury, because a specific neutral sphingomyelinase inhibitor, GW4869 (I mg/kg), did not show any hepatoprotective effect. Notably, a structurally distinct FTI, gliotoxin (I mg/kg), also inhibits Ras activation and reduces serum amounts of ALT and IFN-gamma after APAP dosing. Finally, histological analysis confirmed the hepatoprotective effect f manumycin A and gliotoxin during APAP-induced liver damage. Conclusion: This study identifies a key role for Ras activation and demonstrates the therapeutic efficacy of FTIs during APAP-induced liver injury.

Cooperation of Notch and Ras/MAPK signaling pathways in human breast carcinogenesis

Background: Recent studies have implicated aberrant Notch signaling in breast cancers. Yet, relatively little is known about the pattern of expression of various components of the Notch pathway, or its mechanism of action. To better understand the role of the Notch pathway in breast cancer, we have undertaken a detailed expression analysis of various Notch receptors, their ligands, and downstream targets at different stages of breast cancer progression. Results: We report here that there is a general increase in the expression levels of Notch 1, 2, 4, Jagged1, Jagged2, and Delta-like 4 proteins in breast cancers, with simultaneous upregulation of multiple Notch receptors and ligands in a given cancer tissue. While Notch3 and Delta-like1 were undetectable in normal tissues, moderate to high expression was detected in several cancers. We detected the presence of active, cleaved Notch1, along with downstream targets of the Notch pathway, Hes1/Hes5, in similar to 75% of breast cancers, clearly indicating that in a large proportion of breast cancers Notch signaling is aberrantly activated. Furthermore, we detected cleaved Notch1 and Hes1/5 in early precursors of breast cancers - hyperplasia and ductal carcinoma in situ suggesting that aberrant Notch activation may be an early event in breast cancer progression. Mechanistically, while constitutively active Notch1 alone failed to transform immortalized breast cells, it synergized with the Ras/MAPK pathway to mediate transformation. This cooperation is reflected in vivo, as a subset of cleaved Notch positive tumors additionally expressed phopsho-Erk1/2 in the nuclei. Such cases exhibited high node positivity, suggesting that Notch-Ras cooperation may lead to poor prognosis. Conclusions: High level expression of Notch receptors and ligands, and its increased activation in several breast cancers and early precursors, places Notch signaling as a key player in breast cancer pathogenesis. Its cooperation with the Ras/MAPK pathway in transformation offers combined inhibition of the two pathways as a new modality for breast cancer treatment.

Shift of peak in summer monsoon rainfall over Korea and its association with El Nino-Southern Oscillation

The annual cycle of rainfall over the Korean Peninsula is marked by two peaks: one during July and the other during August. Since the mid-1970s, the maximum rainfall over the Korean Peninsula has shifted from July to August. This shift in rainfall peak was caused by a significant increase of August rainfall after the mid-1970s. The basic reason for this shift has been traced to a change in teleconnection between El Nino-Southern Oscillation (ENSO) and August rainfall. The relationship between August rainfall over Korea and ENSO changed from 1954-1975 (PI) to 1976-2002 (PII). The variability of August rainfall was significantly associated with sea surface temperature (SST) variation over the eastern equatorial Pacific during PI, but this relationship is absent during the PII period. In El Nino years during PI, low-level westerly and southerly wind anomalies are dominant around the East China Sea, which relates to strong August rainfall. In La Nina years during PI, easterly and northerly wind anomalies are dominant. During the PII period, however, westerly and southerly wind anomalies around the East China Sea were responsible for the high August rainfall over the East Asian region, even though La Nina SST conditions were in effect over the eastern Pacific.

On Minimization of Test Application Time for RAS

Conventional Random access scan (RAS) for testing has lower test application time, low power dissipation, and low test data volume compared to standard serial scan chain based design In this paper, we present two cluster based techniques, namely, Serial Input Random Access Scan and Variable Word Length Random Access Scan to reduce test application time even further by exploiting the parallelism among the clusters and performing write operations on multiple bits Experimental results on benchmarks circuits show on an average 2-3 times speed up in test write time and average 60% reduction in write test data volume

Test Application Time Minimization for RAS using Basis Optimization of Column Decoder

Random Access Scan, which addresses individual flip-flops in a design using a memory array like row and column decoder architecture, has recently attracted widespread attention, due to its potential for lower test application time, test data volume and test power dissipation when compared to traditional Serial Scan. This is because typically only a very limited number of random ``care'' bits in a test response need be modified to create the next test vector. Unlike traditional scan, most flip-flops need not be updated. Test application efficiency can be further improved by organizing the access by word instead of by bit. In this paper we present a new decoder structure that takes advantage of basis vectors and linear algebra to further significantly optimize test application in RAS by performing the write operations on multiple bits consecutively. Simulations performed on benchmark circuits show an average of 2-3 times speed up in test write time compared to conventional RAS.

Signatures of Indian ocean Dipole and El Nino-Southern Oscillation events in sea level variations in the Bay of Bengal

We investigate the impact of the Indian Ocean Dipole (IOD) and El Nino and the Southern Oscillation (ENSO) on sea level variations in the North Indian Ocean during 1957-2008. Using tide-gauge and altimeter data, we show that IOD and ENSO leave characteristic signatures in the sea level anomalies (SLAs) in the Bay of Bengal. During a positive IOD event, negative SLAs are observed during April-December, with the SLAs decreasing continuously to a peak during September-November. During El Nino, negative SLAs are observed twice (April-December and November-July), with a relaxation between the two peaks. SLA signatures during negative IOD and La Nina events are much weaker. We use a linear, continuously stratified model of the Indian Ocean to simulate their sea level patterns of IOD and ENSO events. We then separate solutions into parts that correspond to specific processes: coastal alongshore winds, remote forcing from the equator via reflected Rossby waves, and direct forcing by interior winds within the bay. During pure IOD events, the SLAs are forced both from the equator and by direct wind forcing. During ENSO events, they are primarily equatorially forced, with only a minor contribution from direct wind forcing. Using a lead/lag covariance analysis between the Nino-3.4 SST index and Indian Ocean wind stress, we derive a composite wind field for a typical El Nino event: the resulting solution has two negative SLA peaks. The IOD and ENSO signatures are not evident off the west coast of India.

All flavours of El Nino have similar early subsurface origins

The El Nino/Southern Oscillation phenomenon, characterized by anomalous sea surface temperatures and winds in the tropical Pacific, affects climate across the globe(1). El Ninos occur every 2-7 years, whereas the El Nino/Southern Oscillation itself varies on decadal timescales in frequency and amplitude, with a different spatial pattern of surface anomalies(2) each time the tropical Pacific undergoes a regime shift. Recent work has shown that Bjerknes feedback(3,4) (coupling of the atmosphere and the ocean through changes in equatorial winds driven by changes in sea surface temperature owing to suppression of equatorial upwelling in the east Pacific) is not necessary(5) for the development of an El Nino. Thus it is unclear what remains constant through regimes and is crucial for producing the anomalies recognized as El Nino. Here we show that the subsurface process of discharging warm waters always begins in the boreal summer/autumn of the year before the event (up to 18 months before the peak) independent of regimes, identifying the discharge process as fundamental to the El Nino onset. It is therefore imperative that models capture this process accurately to further our theoretical understanding, improve forecasts and predict how the El Nino/Southern Oscillation may respond to climate change.

Coordinate Hyperactivation of Notch1 and Ras/MAPK Pathways Correlates with Poor Patient Survival: Novel Therapeutic Strategy for Aggressive Breast Cancers

Aberrant activation of Notch and Ras pathways has been detected in breast cancers. A synergy between these two pathways has also been shown in breast cell transformation in culture. Yet, the clinical relevance of Notch-Ras cooperation in breast cancer progression remains unexplored. In this study, we show that coordinate hyperactivation of Notch1 and Ras/MAPK pathways in breast cancer patient specimens, as assessed by IHC for cleaved Notch1 and pErk1/2, respectively, correlated with early relapse to vital organs and poor overall survival. Interestingly, majority of such Notch1 (high)Erk(high) cases encompassed the highly aggressive triple-negative breast cancers (TNBC), and were enriched in stem cell markers. We further show that combinatorial inhibition of Notch1 and Ras/MAPK pathways, using a novel mAb against Notch1 and a MEK inhibitor, respectively, led to a significant reduction in proliferation and survival of breast cancer cells compared with individual inhibition. Combined inhibition also abrogated sphere-forming potential, and depleted the putative cancer stem-like cell subpopulation. Most importantly, combinatorial inhibition of Notch1 and Ras/MAPK pathways completely blocked tumor growth in a panel of breast cancer xenografts, including the TNBCs. Thus, our study identifies coordinate hyperactivation of Notch1 and Ras/MAPK pathways as novel biomarkers for poor breast cancer outcome. Furthermore, based on our preclinical data, we propose combinatorial targeting of these two pathways as a treatment strategy for highly aggressive breast cancers, particularly the TNBCs that currently lack any targeted therapeutic module. (C) 2014 AACR.

El Nino and the Indian rainfall in June

We have addressed the question of whether the massive deficit of 42% in rainfall over the Indian region in June 2014 can be attributed primarily to the El Nino. We have shown that the variation of convection over the Northern part of the Tropical West Pacific (NWTP: 120-150E, 20-30N) plays a major role in determining the all-India rainfall in June with deficit (excess) in rainfall associated with enhancement (suppression) of convection over NWTP. In June 2014, the outgoing long wave radiation (OLR) anomaly over this region was unfavourable, whereas in June 2015, the OLR anomaly over NWTP was favourable and the all-India rainfall was 16% higher than the long-term average. We find that during El Nino, when the convection over the equatorial central Pacific intensifies, there is a high propensity for intensification of convection over NWTP. Thus, El Nino appears to have an impact on the rainfall over the Indian region via its impact on the convection over the West Pacific, particularly over NWTP. This occurred in June 2014, which suggests that the large deficit in June 2014, could be primarily attributed to the El Nino acting via intensification of convection over NWTP.