9 research outputs found
Building Resilient Cloud Over Unreliable Commodity Infrastructure
Cloud Computing has emerged as a successful computing paradigm for
efficiently utilizing managed compute infrastructure such as high speed
rack-mounted servers, connected with high speed networking, and reliable
storage. Usually such infrastructure is dedicated, physically secured and has
reliable power and networking infrastructure. However, much of our idle compute
capacity is present in unmanaged infrastructure like idle desktops, lab
machines, physically distant server machines, and laptops. We present a scheme
to utilize this idle compute capacity on a best-effort basis and provide high
availability even in face of failure of individual components or facilities.
We run virtual machines on the commodity infrastructure and present a cloud
interface to our end users. The primary challenge is to maintain availability
in the presence of node failures, network failures, and power failures. We run
multiple copies of a Virtual Machine (VM) redundantly on geographically
dispersed physical machines to achieve availability. If one of the running
copies of a VM fails, we seamlessly switchover to another running copy. We use
Virtual Machine Record/Replay capability to implement this redundancy and
switchover. In current progress, we have implemented VM Record/Replay for
uniprocessor machines over Linux/KVM and are currently working on VM
Record/Replay on shared-memory multiprocessor machines. We report initial
experimental results based on our implementation.Comment: Oral presentation at IEEE "Cloud Computing for Emerging Markets",
Oct. 11-12, 2012, Bangalore, Indi
First-line management of metastatic non-small cell lung cancer: An Indian perspective
Lung cancer has been the most common cancer in the world for several decades. The non-small cell lung cancer (NSCLC) constitutes approximately about 80% of the total cases of lung cancer. Therapeutic interventions in NSCLC have shifted to the target-based approach from histology-based approach, and this has completely changed the face of the management of NSCLC. Developing countries, such as India, have very limited data compiled about the prevalence and treatment practices of lung cancer, despite a large burden of the disease. However, in recent times, there has been a lot of data generated in this regard. This article is an attempt to collate and shine light on the available data for the first-line treatment of NSCLC in India keeping in mind the current standards of care in this area
N-aryl-2-aminobenzimidazoles:Novel, efficacious, antimalarial lead compounds
From the phenotypic screening of the AstraZeneca corporate compound collection, N-aryl-2-aminobenzimidazoles have emerged as novel hits against the asexual blood stage of Plasmodium falciparum (Pf). Medicinal chemistry optimization of the potency against Pf and ADME properties resulted in the identification of 12 as a lead molecule. Compound 12 was efficacious in the P. berghei (Pb) model of malaria. This compound displayed an excellent pharmacokinetic profile with a long half-life (19 h) in rat blood. This profile led to an extended survival of animals for over 30 days following a dose of 50 mg/kg in the Pb malaria model. Compound 12 retains its potency against a panel of Pf isolates with known mechanisms of resistance. The fast killing observed in the in vitro parasite reduction ratio (PRR) assay coupled with the extended survival highlights the promise of this novel chemical class for the treatment of malaria.No Full Tex
A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria
Malaria is one of the most significant causes of childhood mortality, but disease control efforts are threatened by resistance of the Plasmodium parasite to current therapies. Continued progress in combating malaria requires development of new, easy to administer drug combinations with broad-ranging activity against all manifestations of the disease. DSM265, a triazolopyrimidine-based inhibitor of the pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH), is the first DHODH inhibitor to reach clinical development for treatment of malaria. We describe studies profiling the biological activity, pharmacological and pharmacokinetic properties, and safety of DSM265, which supported its advancement to human trials. DSM265 is highly selective toward DHODH of the malaria parasite Plasmodium, efficacious against both blood and liver stages of P. falciparum, and active against drug-resistant parasite isolates. Favorable pharmacokinetic properties of DSM265 are predicted to provide therapeutic concentrations for more than 8 days after a single oral dose in the range of 200 to 400 mg. DSM265 was well tolerated in repeat-dose and cardiovascular safety studies in mice and dogs, was not mutagenic, and was inactive against panels of human enzymes/receptors. The excellent safety profile, blood- and liver-stage activity, and predicted long half-life in humans position DSM265 as a new potential drug combination partner for either single-dose treatment or once-weekly chemoprevention. DSM265 has advantages over current treatment options that are dosed daily or are inactive against the parasite liver stage
<i>N</i>‑Aryl-2-aminobenzimidazoles: Novel, Efficacious, Antimalarial Lead Compounds
From
the phenotypic screening of the AstraZeneca corporate compound
collection, <i>N</i>-aryl-2-aminobenzimidazoles have emerged
as novel hits against the asexual blood stage of <i>Plasmodium
falciparum</i> (<i>Pf</i>). Medicinal chemistry optimization
of the potency against <i>Pf</i> and ADME properties resulted
in the identification of <b>12</b> as a lead molecule. Compound <b>12</b> was efficacious in the <i>P. berghei</i> (<i>Pb</i>) model of malaria. This compound displayed an excellent
pharmacokinetic profile with a long half-life (19 h) in rat blood.
This profile led to an extended survival of animals for over 30 days
following a dose of 50 mg/kg in the <i>Pb</i> malaria model.
Compound <b>12</b> retains its potency against a panel of <i>Pf</i> isolates with known mechanisms of resistance. The fast
killing observed in the <i>in vitro</i> parasite reduction
ratio (PRR) assay coupled with the extended survival highlights the
promise of this novel chemical class for the treatment of malaria
Aminoazabenzimidazoles, a Novel Class of Orally Active Antimalarial Agents
Whole-cell high-throughput
screening of the AstraZeneca compound
library against the asexual blood stage of Plasmodium
falciparum (<i>Pf</i>) led to the identification
of amino imidazoles, a robust starting point for initiating a hit-to-lead
medicinal chemistry effort. Structure–activity relationship
studies followed by pharmacokinetics optimization resulted in the
identification of <b>23</b> as an attractive lead with good
oral bioavailability. Compound <b>23</b> was found to be efficacious
(ED<sub>90</sub> of 28.6 mg·kg<sup>–1</sup>) in the humanized P. falciparum mouse model of malaria (<i>Pf</i>/SCID model). Representative compounds displayed a moderate to fast
killing profile that is comparable to that of chloroquine. This series
demonstrates no cross-resistance against a panel of <i>Pf</i> strains with mutations to known antimalarial drugs, thereby suggesting
a novel mechanism of action for this chemical class