Cardiovascular safety of protein kinase inhibitors: putting their “QT-phobia” in perspective

Many potentially valuable drugs, including protein kinase inhibitors (PKI), risk being dropped from further development, without exploration of their clinical benefits, if early studies show these drugs to inhibit hERG channel and therefore, to have a potential for prolonging ventricular repolarisation (QT interval). This QT-phobia results from a perceived possibility of the clinical risks of QT-related ventricular proarrhythmia, further aggravated by uncertainties surrounding the regulatory evaluation of the risk and either approvability or restrictive labelling of the drug concerned. In reality, QT interval prolongation per se is only an imperfect surrogate of the proarrhythmia risk which is much smaller than perceived and compared to their other cardiovascular and non-cardiovascular risks. PKI-induced clinical hepatotoxicity, also evaluated on the basis of surrogate markers (serum transaminases and bilirubin) is another risk that far exceeds any risk arising from PKI-induced QT interval prolongation. This review of the currently approved 28 PKIs places the QT-phobia surrounding the development of PKIs in its perspective by juxta-positioning their potential to induce ventricular dysfunction, arterial thrombotic events and hepatotoxicity. Available evidence suggests that hERG channel may prove to be a valuable therapeutic target in oncology. Therefore, the development, approval and labelling of such vital oncology drugs requires careful assessment of their benefits and their risk/benefit generally, without being overtly consumed by their potential QT-liability, in terms of their more direct consequences on clinically relevant endpoints of morbidity, mortality and quality of life

Fundamental Limits on Communication for Oblivious Updates in Storage Networks

In distributed storage systems, storage nodes intermittently go offline for numerous reasons. On coming back online, nodes need to update their contents to reflect any modifications to the data in the interim. In this paper, we consider a setting where no information regarding modified data needs to be logged in the system. In such a setting, a 'stale' node needs to update its contents by downloading data from already updated nodes, while neither the stale node nor the updated nodes have any knowledge as to which data symbols are modified and what their value is. We investigate the fundamental limits on the amount of communication necessary for such an "oblivious" update process. We first present a generic lower bound on the amount of communication that is necessary under any storage code with a linear encoding (while allowing non-linear update protocols). This lower bound is derived under a set of extremely weak conditions, giving all updated nodes access to the entire modified data and the stale node access to the entire stale data as side information. We then present codes and update algorithms that are optimal in that they meet this lower bound. Next, we present a lower bound for an important subclass of codes, that of linear Maximum-Distance-Separable (MDS) codes. We then present an MDS code construction and an associated update algorithm that meets this lower bound. These results thus establish the capacity of oblivious updates in terms of the communication requirements under these settings.Comment: IEEE Global Communications Conference (GLOBECOM) 201

Interference Alignment in Regenerating Codes for Distributed Storage: Necessity and Code Constructions

Regenerating codes are a class of recently developed codes for distributed storage that, like Reed-Solomon codes, permit data recovery from any arbitrary k of n nodes. However regenerating codes possess in addition, the ability to repair a failed node by connecting to any arbitrary d nodes and downloading an amount of data that is typically far less than the size of the data file. This amount of download is termed the repair bandwidth. Minimum storage regenerating (MSR) codes are a subclass of regenerating codes that require the least amount of network storage; every such code is a maximum distance separable (MDS) code. Further, when a replacement node stores data identical to that in the failed node, the repair is termed as exact. The four principal results of the paper are (a) the explicit construction of a class of MDS codes for d = n-1 >= 2k-1 termed the MISER code, that achieves the cut-set bound on the repair bandwidth for the exact-repair of systematic nodes, (b) proof of the necessity of interference alignment in exact-repair MSR codes, (c) a proof showing the impossibility of constructing linear, exact-repair MSR codes for d < 2k-3 in the absence of symbol extension, and (d) the construction, also explicit, of MSR codes for d = k+1. Interference alignment (IA) is a theme that runs throughout the paper: the MISER code is built on the principles of IA and IA is also a crucial component to the non-existence proof for d < 2k-3. To the best of our knowledge, the constructions presented in this paper are the first, explicit constructions of regenerating codes that achieve the cut-set bound.Comment: 38 pages, 12 figures, submitted to the IEEE Transactions on Information Theory;v3 - The title has been modified to better reflect the contributions of the submission. The paper is extensively revised with several carefully constructed figures and example

Condensed heterotricycles: synthesis of pyrazolo[3,4-c]qumoline derivatives

Pyrazol[3,4-c]quinoline 4a is obtained from 4-(2-riitrophenyl)pyrazole-3-carboxylate (3a) by reduction followed by thermal cyclization. 4a undergoes aminoalkylation uniquely at N(3) to form 4b-d, as shown by I3C NMR. Pyrazoles 3a and 3c are methylated at N(2) to 6a and 6b respectively which are re-ductively cyclized to pyrazoloquinolones 7a and 7b. The later are transformed into amino derivatives 8b-d and 8g,h via chloro compounds 8a and 8f. The.amino alkoxypyrazoloquinoline (8e) is obtained from 8a or the lactam 7a. Cyclic hydroxamic acids 7c and 7d are prepared from the nitropyrazoles 6a and 6b by using NaBH4 and Pd - C. A second synthesis of die pyrazolo[3,4-c]quinoline ring system consists of heating mercaptoacid (8) with methyl or phenyl hydrazine when 10a or 10b is obtained. Attempts to convert the pyrazole carboxylate 13a into an isomeric pyrazoloisoquinoline system 12 via the isocyan-ate 13d resulted only in the formation of bis-urea 14

Explicit Construction of Optimal Exact Regenerating Codes for Distributed Storage

Erasure coding techniques are used to increase the reliability of distributed storage systems while minimizing storage overhead. Also of interest is minimization of the bandwidth required to repair the system following a node failure. In a recent paper, Wu et al. characterize the tradeoff between the repair bandwidth and the amount of data stored per node. They also prove the existence of regenerating codes that achieve this tradeoff. In this paper, we introduce Exact Regenerating Codes, which are regenerating codes possessing the additional property of being able to duplicate the data stored at a failed node. Such codes require low processing and communication overheads, making the system practical and easy to maintain. Explicit construction of exact regenerating codes is provided for the minimum bandwidth point on the storage-repair bandwidth tradeoff, relevant to distributed-mail-server applications. A subspace based approach is provided and shown to yield necessary and sufficient conditions on a linear code to possess the exact regeneration property as well as prove the uniqueness of our construction. Also included in the paper, is an explicit construction of regenerating codes for the minimum storage point for parameters relevant to storage in peer-to-peer systems. This construction supports a variable number of nodes and can handle multiple, simultaneous node failures. All constructions given in the paper are of low complexity, requiring low field size in particular.Comment: 7 pages, 2 figures, in the Proceedings of Allerton Conference on Communication, Control and Computing, September 200

EVALUATION OFANTI-OXIDANT AND ANTI-ACNE ACTIVITIES (IN-VITRO) OF THE FORMULATED HERBAL GELS

Objective: The objective of the present study was to evaluate the anti-oxidant and anti-acne activities (in-vitro) of the formulated herbal gels. Methods: Herbal extracts and volatile oils were prepared and procured. Preliminary screenings for the anti-oxidant and anti-acne activities (in-vitro) were carried out to select the suitable candidates for the preparation of anti-acne herbal gels. Gels were further evaluated for the activities. Results: The herbal gel (F2) containing the herbal extracts (Azadirachtaindica, Ocmium sanctum, Curcuma longa) each (1%) and volatile oils (Melaleucaalternifoliae, Salviaesclareae and Citrus sinensis) each (0.05%) showed maximum anti-oxidant activity (IC50 value 0.407 mg) amongst all four gels. Significant anti-acne activity against P. acne and S. epidermidis was showed by F2 when compared with the marketed synthetic gel (Clindac gel). Conclusion: The study proves that the herbal actives used in the formulation have promising anti-oxidant and anti-acne activity