Transcription factors that mediate epithelial-mesenchymal transition lead to multidrug resistance by upregulating ABC transporters

Development of multidrug resistance (MDR) is a major deterrent in the effective treatment of metastatic cancers by chemotherapy. Even though MDR and cancer invasiveness have been correlated, the molecular basis of this link remains obscure. We show here that treatment with chemotherapeutic drugs increases the expression of several ATP binding cassette transporters (ABC transporters) associated with MDR, as well as epithelial-mesenchymal transition (EMT) markers, selectively in invasive breast cancer cells, but not in immortalized or non-invasive cells. Interestingly, the mere induction of an EMT in immortalized and non-invasive cell lines increased their expression of ABC transporters, migration, invasion, and drug resistance. Conversely, reversal of EMT in invasive cells by downregulating EMT-inducing transcription factors reduced their expression of ABC transporters, invasion, and rendered them more chemosensitive. Mechanistically, we demonstrate that the promoters of ABC transporters carry several binding sites for EMT-inducing transcription factors, and overexpression of Twist, Snail, and FOXC2 increases the promoter activity of ABC transporters. Furthermore, chromatin immunoprecipitation studies revealed that Twist binds directly to the E-box elements of ABC transporters. Thus, our study identifies EMT inducers as novel regulators of ABC transporters, thereby providing molecular insights into the long-standing association between invasiveness and MDR. Targeting EMT transcription factors could hence serve as novel strategies to curb both metastasis and the associated drug resistance. Cell Death and Disease (2011) 2, e179; doi:10.1038/cddis.2011.61; published online 7 July 2011

Efficient syntheses of benzothiazepines as antagonists for the mitochondrial sodium-calcium exchanger: Potential therapeutics for type II diabetes

Type II diabetes mellitus is a chronic metabolic disorder that can lead to serious cardiovascular, renal, neurologic, and retinal complications. While several drugs are currently prescribed to treat type II diabetes, their efficacy is limited by mechanism-related side effects (weight gain, hypoglycemia, gastrointestinal distress), inadequate efficacy for use as monotherapy, and the development of tolerance to the agents. Consequently, combination therapies are frequently employed to effectively regulate blood glucose levels. We have focused on the mitochondrial sodium-calcium exchanger (mNCE) as a novel target for diabetes drug discovery. We have proposed that inhibition of the mNCE can be used to regulate calcium flux across the mitochondrial membrane, thereby enhancing mitochondrial oxidative metabolism, which in turn enhances glucose-stimulated insulin secretion (GSIS) in the pancreatic beta-cell. In this paper, we report the facile synthesis of benzothiazepines and derivatives by S-alkylation using 2-aminobenzhydrols. The syntheses of other bicyclic analogues based on benzothiazepine, benzothiazecine, benzodiazecine, and benzodiazepine templates are also described. These compounds have been evaluated for their inhibition of mNCE activity, and the results from the structure-activity relationship (SAR) studies are discussed.

Investigation on the Sources of Reflection at the Junction of Tall Grounded Object and Lightning Channel

During lightning strike to a tall grounded object (TGO), reflections of current waves are known to occur at either ends of the TGO. These reflection modify the channel current and hence, the lightning electromagnetic fields. This study aims to identify the possible contributing factors to reflection at a TGO-channel junction for the current waves ascending on the TGO. Possible sources of reflection identified are corona sheath and discontinuity of resistance and radius. For analyzing the contribution of corona sheath and discontinuity of resistance at the junction, a macroscopic physical model for the return stroke developed in our earlier work is employed. NEC-2D is used for assessing the contribution of abrupt change in radii at a TGO-channel junction. The wire-cage model adopted for the same is validated using laboratory experiments. Detailed investigation revealed the following. The main contributor for reflection at a TGO-channel junction is the difference between TGO and channel core radii. Also, the discontinuity of resistance at a TGO-channel junction can be of some relevance only for the first microsecond regime. Further, corona sheath does not play any significant role in the reflection.

Transmission of correlated sources over fading multiple access channel

In this paper we address the problem of transmission of correlated sources over a fading multiple access channel (MAC). We provide sufficient conditions for transmission with given distortions. Next these conditions are specialized to a Gaussian MAC (GMAC). Transmission schemes for discrete and Gaussian sources over a fading GMAC are considered. Various power allocation strategies are also compared. Keywords: Fading MAC, Power allocation, Random TDMA, Amplify and Forward, Correlated sources.

Finite Signal-set Capacity of Two-user Gaussian Multiple Access Channel

The capacity region of a two-user Gaussian Multiple Access Channel (GMAC) with complex finite input alphabets and continuous output alphabet is studied. When both the users are equipped with the same code alphabet, it is shown that, rotation of one of the user’s alphabets by an appropriate angle can make the new pair of alphabets not only uniquely decodable, but will result in enlargement of the capacity region. For this set-up, we identify the primary problem to be finding appropriate angle(s) of rotation between the alphabets such that the capacity region is maximally enlarged. It is shown that the angle of rotation which provides maximum enlargement of the capacity region also minimizes the union bound on the probability of error of the sumalphabet and vice-verse. The optimum angle(s) of rotation varies with the SNR. Through simulations, optimal angle(s) of rotation that gives maximum enlargement of the capacity region of GMAC with some well known alphabets such as M-QAM and M-PSK for some M are presented for several values of SNR. It is shown that for large number of points in the alphabets, capacity gains due to rotations progressively reduce. As the number of points N tends to infinity, our results match the results in the literature wherein the capacity region of the Gaussian code alphabet doesn’t change with rotation for any SNR.

Estimation of BT interference and equivalent channel tap in multipath fading channel

One of the major sources of interference for WLANs operating in 2.4GHz unlicensed ISM is Bluetooth (BT). Though OFDM based WLAN's have features like strong immunity to multipath channel effects, its performance detoriates severely whenever there is BT operating nearby. Even for high SIR (Signal to Interference Ratio), performance does not improve much because WLAN is not able to estimate correctly all its channel parameters in presence of BT interference. So, in this paper, the authors propose an algorithm for estimating BT interference and equivalent channel filter tap values.

Texture and grain boundary character distribution during Equal Channel Angular Extrusion of some two-phase copper alloys

In the present work, a thorough investigation of evolution of microstructure and texture has been carried out to elucidate the evolution of texture and grain boundary character distribution (GBCD) during Equal Channel Angular Extrusion (ECAE) of some model two-phase materials, namely Cu-0.3Cr and Cu-40Zn. Texture of Cu-0.3Cr alloy is similar to that reported for pure copper. On the other hand, in Cu-40Zn alloy, texture evolution in α and β (B2) phases are interdependent. In Cu-0.3Cr alloy, there is a considerable decreases in volume fraction of low angle boundaries (LAGBs), only a slight increase in CSL boundaries, but increase in high angle grain boundaries (HAGBs) from 1 pass to 4 passes for both the routes. In the case of Cu-40Zn alloy, there is an appreciable increase in CSL volume fraction.

Source-channel coding for Gaussian sources over a Gaussian multiple access channel

We consider the problem of distributed joint source-channel coding of correlated Gaussian sources over a Gaussian Multiple Access Channel (MAC). There may be side information at the encoders and/or at the decoder. First we specialize a general result in [16] to obtain sufficient conditions for reliable transmission over a Gaussian MAC. This system does not satisfy the source channel separation. Thus, next we study and compare three joint source channel coding schemes available in literature.

Spectral Efficiency of Channel-Aware Schedulers in Non-identical Composite Links with Interference

Accurate system planning and performance evaluation requires knowledge of the joint impact of scheduling, interference, and fading. However, current analyses either require costly numerical simulations or make simplifying assumptions that limit the applicability of the results. In this paper, we derive analytical expressions for the spectral efficiency of cellular systems that use either the channel-unaware but fair round robin scheduler or the greedy, channel-aware but unfair maximum signal to interference ratio scheduler. As is the case in real deployments, non-identical co-channel interference at each user, both Rayleigh fading and lognormal shadowing, and limited modulation constellation sizes are accounted for in the analysis. We show that using a simple moment generating function-based lognormal approximation technique and an accurate Gaussian-Q function approximation leads to results that match simulations well. These results are more accurate than erstwhile results that instead used the moment-matching Fenton-Wilkinson approximation method and bounds on the Q function. The spectral efficiency of cellular systems is strongly influenced by the channel scheduler and the small constellation size that is typically used in third generation cellular systems.

Channel Precoding for STBCs from Generalized Pseudo Orthogonal Designs

Statistical information about the wireless channel can be used at the transmitter side to enhance the performance of MIMO systems. This paper addresses how the concept of channel precoding can be used to enhance the performance of STBCs from Generalized Pseudo Orthogonal Designs which were first introduced by Zhu and Jafarkhani. Such designs include some important classes of STBCs that are directly derivable from Quasi-Orthogonal Designs and Co-ordinate Interleaved Orthogonal Designs.

Tracking analysis of an LMS decision feedback equalizer for a wireless channel

We consider a time varying wireless fading channel, equalized by an LMS Decision Feedback equalizer (DFE). We study how well this equalizer tracks the optimal MMSEDFE (Wiener) equalizer. We model the channel by an Autoregressive (AR) process. Then the LMS equalizer and the AR process are jointly approximated by the solution of a system of ODEs (ordinary differential equations). Using these ODEs, we show via some examples that the LMS equalizer moves close to the instantaneous Wiener filter after initial transience. We also compare the LMS equalizer with the instantaneous optimal DFE (the commonly used Wiener filter) designed assuming perfect previous decisions and computed using perfect channel estimate (we will call it as IDFE). We show that the LMS equalizer outperforms the IDFE almost all the time after initial transience.

High-rate analysis of channel-optimized vector quantization

High-rate analysis of channel-optimized vector quantizationThis paper considers the high-rate performance of channel optimized source coding for noisy discrete symmetric channels with random index assignment. Specifically, with mean squared error (MSE) as the performance metric, an upper bound on the asymptotic (i.e., high-rate) distortion is derived by assuming a general structure on the codebook. This structure enables extension of the analysis of the channel optimized source quantizer to one with a singular point density: for channels with small errors, the point density that minimizes the upper bound is continuous, while as the error rate increases, the point density becomes singular. The extent of the singularity is also characterized. The accuracy of the expressions obtained are verified through Monte Carlo simulations.