Small-molecule Inhibition of KRAS Through Conformational Selection

Mutations in KRAS account for about 20% of human cancers. Despite the major progress in recent years toward the development of KRAS inhibitors, including the discovery of covalent inhibitors of the G12C KRAS variant for the treatment of non-small-cell lung cancer, much work remains to be done to discover broad-acting inhibitors to treat many other KRAS-driven cancers. In a previous report, we showed that a 308.4 Da small-molecule ligand [(2R)-2-(N\u27-(1H-indole-3-carbonyl)hydrazino)-2-phenyl-acetamide] binds to KRAS with low micro-molar affinity [Chem. Biol. Drug Des.2019; 94(2):1441-1456]. Binding of this ligand, which we call ACA22, to the p1 pocket of KRAS and its interactions with residues at beta-strand 1 and the switch loops have been supported by data from nuclear magnetic resonance spectroscopy and microscale thermophoresis experiments. However, the inhibitory potential of the compound was not demonstrated. Here, we show that ACA22 inhibits KRAS-mediated signal transduction in cells expressing wild type (WT) and G12D mutant KRAS and reduces levels of guanosine triphosphate-loaded WT KRAS more effectively than G12D KRAS. We ruled out the direct effect on nucleotide exchange or effector binding as possible mechanisms of inhibition using a variety of biophysical assays. Combining these observations with binding data that show comparable affinities of the compound for the active and inactive forms of the mutant but not the WT, we propose conformational selection as a possible mechanism of action of ACA22

Sustainability as corporate culture of a brand for superior performance

This is the post-print version of the final paper published in the Journal of World Business. The published article is available from the link below. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. Copyright @ 2012 Elsevier B.V.Sustainability research highlights new challenges and opportunities for businesses. This paper reviews the literature to understand the ability of sustainable green initiatives when practiced as a corporate culture to individually create new opportunities for operations, management and marketing. According to current research, business opportunities exclusively available to different functions of a firm can drive its performance. The role of marketing in the achievement of superior performance by virtue of sustainability practices is also explained by the existing literature. Branding literature, however, fails to explain the influence of a brand on sustainability-driven opportunities available to a firm for superior performance. The objective of this study is to explore if a brand can strengthen the ability of sustainability-based green initiatives of managers to drive opportunities available to a firm for superior performance. A conceptual framework grounded in the triple bottom line theory is presented based on the assumption that brand as a stimulating factor can accelerate the conversion of opportunities available to a business into superior performance. Academic and managerial perspectives have been used to draw upon the implications of the model. Both practitioners and academic researchers will benefit from future research on this topic

Evaluation of ultrasound guided verses nerve stimulator technique of interscalene brachial plexus block: insights from Indian multi-super specialty hospital

Background: To provide adequate intraoperative anaesthesia and postoperative analgesia for orthopaedic surgery continues to be a procedural challenge. The administration of brachial plexus anaesthesia can be facilitated through nerve stimulation or by ultrasound guidance. Hence study was conducted to compare differences in these techniques in patients undergoing interscalene brachial plexus block (ISSB).Methods: In this prospective, randomized, observer-blinded study, 60 patients (Male=41, Female=19) were scheduled for orthopaedic shoulder and upper arm surgeries matching inclusion and exclusion criteria. Patients were randomly allocated to either Ultrasound (US, n=30) group or Nerve Stimulator (NS, n=30) group through a computer-generated randomization.Results: There was significant difference between US and NS group with respect to average number of attempts taken, block performance time (BPT), onset of sensory and motor block, duration of motor block and patient satisfaction score. Whereas not much significant difference was observed in duration of sensory block, block success rate and incidence of post operative side effects.Conclusions: The results suggest that US guided ISBB is significantly superior to NS guided block in terms of faster onset of action; lower number of attempts to locate Interscalene brachial plexus; longer duration of block and overall success rate with favourable tolerability at real-life scenario

Seroprevalence and risk factors associated with bovine brucellosis in western Uttar Pradesh, India

The present study was conducted to estimate the prevalence of brucellosis in cattle and buffaloes of western Uttar Pradesh, India and possible risk factors associated with it. Blood samples collected from 1,019 animals (dairy cattle and buffaloes) of different age and sex from 17 districts of western Uttar Pradesh, India where no vaccination against brucellosis is practiced were subjected to indirect ELISA for detection of Brucella antibodies. The overall mean seropositivity was 12.37% with seropositivity in unorganized and organized farms 4.08% and 24.88%, respectively. The young calves were having significantly higher seropositivity (10.38%) and it further increased in sexually matured adults (12.71%) in comparison to older animals (9.17%). Overall seropositivity and risk factors logistic regression analyses showed that species and farming type (organized and unorganized) had significant effect and sex of animals and their age group had no significant effect on the positivity of brucellosis. In absence of any vaccination presence of circulating antibodies against Brucella in all age group of animals indicated the natural circulation of infection in the state. Study indicated an urgent need of policy for prevention and control of brucellosis in dairy animals

An Interventional Study on Comprehensive Emergency Care and Trauma Registry for Road Traffic Injuries in India: A Protocol

Road traffic injuries (RTIs) stands as one of the leading causes of mortality and morbidity across the globe. Effective injury surveillance systems and pre-hospital and in-hospital interventions set up in developing countries have shown promising results in controlling the problem. This study aimed to standardise and evaluate an evidence-based intervention for safety, efficacy and quality of post-crash pre-hospital and in-hospital trauma care services to improve the outcome in RTI victims. In addition, it establishes the android-based trauma registry for effective RTI surveillance. This multi-centric, prospective, observational study is commissioned by the Indian Council of Medical Research (ICMR) as a National Task Force Project. This study is being conducted in five sites, viz., Anand, Bengaluru, Delhi, Lucknow and Thrissur located across India. Each centre will have a level I, two level II and three level III trauma hospitals. The study will be carried out in four phases namely: i) preparatory phase, ii) trauma registry establishment and pre-intervention data collection, iii) intervention and iv) impact evaluation. The preparatory phase, which lasts for four months includes the situational analysis pertaining to managing RTIs. Trauma registry will be initiated from the fifth month. Pre-intervention data will be collected for six months. The intervention will be conducted for six months in the form of prehospital notification, training for trauma care providers and trauma care quality improvement. Post-intervention data collection will continue for 12 months and the impact of the intervention will be assessed. The primary outcome measure will be early preventable mortality, defined as death at 24 hours after admission for patients with a calculated probability of survival >50% based on their injury severity score

Global delivery models: the role of talent, speed and time zones in the global outsourcing industry

Global delivery models (GDMs) are transforming the global IT and business process outsourcing industry. GDMs are a new form of client-specific investment promoting service integration with clients by combining client proximity with time-zone spread for 24/7 service operations. We investigate antecedents and contingencies of setting up GDM structures. Based on comprehensive data we show that providers are likely to establish GDM location configurations when clients value access to globally distributed talent and speed of service delivery, in particular when services are highly commoditized. Findings imply that coordination across time zones increasingly affects international operations in business-to-business and born-global industries

Detonating Cord for Flux Compression Generation using Electrical Detonator No. 33

The paper highlights the use of electrical detonators for magnetic flux compression generator applications which requires synchronisation of two events with precise time delay of tens of ms and jitter within a few ms. These requirements are generally achieved by exploding bridge wire type detonators which are difficult to develop and are not commercially available. A technique has been developed using commercially available electrical detonator no. 33 to synchronise between peak of seed current in stator coil and detonation of explosive charge in armature. In present experiments, electrical signal generated by self-shorting pin due to bursting of electrical detonator has been used to trigger the capacitor discharge and the detonating cord of known length has been used to incorporate predetermined delay to synchronise the events. It has been demonstrated that using electrical detonator and known length of detonating cord, the two events can be synchronised with predetermined delay between 31 and 251 ms with variation of ± 0.5ms. The technique developed is suitable for defence applications like generation of high power microwaves using explosive driven magnetic flux compression generators.Defence Science Journal, 2011, 61(1), pp.19-24, DOI:http://dx.doi.org/10.14429/dsj.61.3

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Fibrosing cholestatic hepatitis in renal transplant recipient with CMV infection: A case report

Abstract. Fibrosing cholestatic hepatitis (FCH) is an uncommon complication of renal transplantation. It is usually associated with hepatitis B and C viral infection. It is further rare in renal transplantation in absence of HBV and HCV infection. To the best of our knowledge, only three cases of FCH in renal transplantation, which were both HBV and HCV negative, have been reported to date. Out of these, two cases were diagnosed to have CMV infection and the third was attributed to azathioprin. We are presenting another case of FCH in a renal transplant recipient with CMV infection