| 1. |
|
|
| 2. |
- Alvarez, Mariano J., et al.
(författare)
-
A precision oncology approach to the pharmacological targeting of mechanistic dependencies in neuroendocrine tumors
- 2018
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:7, s. 979-989
-
Tidskriftsartikel (refereegranskat)abstract
- We introduce and validate a new precision oncology framework for the systematic prioritization of drugs targeting mechanistic tumor dependencies in individual patients. Compounds are prioritized on the basis of their ability to invert the concerted activity of master regulator proteins that mechanistically regulate tumor cell state, as assessed from systematic drug perturbation assays. We validated the approach on a cohort of 212 gastroenteropancreatic neuroendocrine tumors (GEP-NETs), a rare malignancy originating in the pancreas and gastrointestinal tract. The analysis identified several master regulator proteins, including key regulators of neuroendocrine lineage progenitor state and immunoevasion, whose role as critical tumor dependencies was experimentally confirmed. Transcriptome analysis of GEP-NET-derived cells, perturbed with a library of 107 compounds, identified the HDAC class I inhibitor entinostat as a potent inhibitor of master regulator activity for 42% of metastatic GEP-NET patients, abrogating tumor growth in vivo. This approach may thus complement current efforts in precision oncology.
|
|
| 3. |
- Biswas, B., et al.
(författare)
-
Near-infrared emissive cyanine probes for selective visualization of the physiological and pathophysiological modulation of albumin levels
- 2022
-
Ingår i: Journal of materials chemistry. B. - : Royal Society of Chemistry (RSC). - 2050-750X .- 2050-7518.
-
Tidskriftsartikel (refereegranskat)abstract
- With the promising advantages of the near-infrared region (NIR) emissive markers for serum albumin becoming very prominent recently, we devised CyG-NHS as the cyanine derived longest NIR-I emissive optical marker possessing albumin selective recognition ability in diverse biological milieu. Multiscale modeling involving molecular docking, molecular dynamics, and implicit solvent binding free energy calculations have been employed to gain insights into the unique binding ability of the developed probe at domain-I of albumin, in contrast to the good number of domain IIA or IIIA binding probes available in the literature reports. The binding free energy was found to be −31.8 kcal mol−1 majorly predominated by hydrophobic interactions. Besides, the conformational dynamics of CyG-NHS in an aqueous medium and the albumin microenvironment have been comprehensively studied and discussed. The potentiality of this optical platform to monitor the intracellular albumin levels in human hepatoma (HepG2) cells in different pathophysiological states has been demonstrated here. Also, the competency of the phenformin drug in restoring the albumin levels in chronic hyperinsulinemic and hypercholesterolemic in vitro models has been established through the visualization approach. Altogether, the findings of this study throw light on the significance of the development of a suitable optical marker for the visualization of critical bioevents related to albumin.
|
|
| 4. |
- Mathews, T.S, et al.
(författare)
-
Integration of functional reliability analysis with hardware reliability : An application to safety grade decay heat removal system of Indian 500 MWe PFBR
- 2009
-
Ingår i: Annals of Nuclear Energy. - : Elsevier BV. - 0306-4549 .- 1873-2100. ; 36:4, s. 481-492
-
Tidskriftsartikel (refereegranskat)abstract
- A passive system can fail either due to classical mechanical failure of components, referred to as hardware failure, or due to the failure of physical phenomena to fulfill the intended function, referred to as functional failure. In this paper a methodology is discussed for the integration of these two kinds of unreliability and applied to evaluate the integrated failure probability of the passive decay heat removal system of Indian 500 MWe prototype fast breeder reactor (PFBR). The probability of occurrence of various system hardware configurations is evaluated using the fault tree method and functional failure probabilities on the corresponding configurations are determined based on the overall approach reported in the reliability methods for passive system (RMPS) project. The variation of functional reliability with time, which is coupled to the probability of occurrence of various hardware system configurations is studied and incorporated in the integrated reliability analysis. It is observed that this consideration of the dependence of functional reliability on time will give significant advantages on system reliability. The integrated reliability analysis is also explained using an event tree. The impact of the provision for forced circulation in the primary circuit on functional reliability is also studied with this procedure and it is found that the forced circulation capability helps to bring down the total decay heat removal failure probability by lowering the peak temperatures after the reactor shut down.
|
|
| 5. |
- Samanta, S., et al.
(författare)
-
Naphthalene Monoimide Derivative Ameliorates Amyloid Burden and Cognitive Decline in a Transgenic Mouse Model of Alzheimer's Disease
- 2021
-
Ingår i: Advanced Therapeutics. - : Blackwell Publishing Ltd. - 2366-3987. ; 4:4
-
Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is a major neurodegenerative disorder and the leading cause of dementia worldwide. Predominantly, misfolding and aggregation of amyloid-β (Aβ) peptides associated with multifaceted toxicity is the neuropathological hallmark of AD pathogenesis and, thus the primary therapeutic target to ameliorate neuronal toxicity and cognitive deficits. Herein, the design, synthesis, and evaluation of small molecule inhibitors with naphthalene monoimide scaffold to ameliorate in vitro and in vivo amyloid induced neurotoxicity are reported. The detailed studies establish TGR63 as the lead candidate to rescue neuronal cells from amyloid toxicity. The in silico studies show the disruption of salt bridges and intermolecular hydrogen bonding interactions within Aβ42 fibrils by the interaction of TGR63, causing destabilization of Aβ42 assembly. Remarkably, TGR63 treatment shows a significant reduction in cortical and hippocampal amyloid burden in the progressive stages of APP/PS1 AD mice brain. Various behavioral tests demonstrate rescued cognitive deficits. The excellent biocompatibility, blood–brain barrier permeability, and therapeutic efficacy to reduce the amyloid burden make TGR63 a promising candidate for the treatment of AD.
|
|
| 6. |
- Arul, A.J, et al.
(författare)
-
Reliability analysis of safety grade decay heat removal system of Indian prototype fast breeder reactor
- 2006
-
Ingår i: Annals of Nuclear Energy. - : Elsevier BV. - 0306-4549. ; 33:2, s. 180-188
-
Tidskriftsartikel (refereegranskat)abstract
- The 500MW Indian pool type Prototype Fast Breeder Reactor (PFBR), is provided with two independent and diverse Decay Heat Removal (DHR) systems viz., Operating Grade Decay Heat Removal System (OGDHRS) and Safety Grade Decay Heat Removal System (SGDHRS). OGDHRS utilizes the secondary sodium loops and Steam–Water System with special decay heat removal condensers for DHR function. The unreliability of this system is of the order of 0.1–0.01. The safety requirements of the present generation of fast reactors are very high, and specifically for DHR function the failure frequency should be less than 1E-7/ry. Therefore, a passive SGDHR system using four completely independent thermo-siphon loops in natural convection mode is provided to ensure adequate core cooling for all Design Basis Events. The very high reliability requirement for DHR function is achieved mainly with the help of SGDHRS. This paper presents the reliability analysis of SGDHR system. Analysis is performed by Fault Tree method using "CRAFT" software developed at Indira Gandhi Centre for Atomic Research. This software has special features for compact representation and CCF analysis of high redundancy safety systems encountered in nuclear reactors. Common Cause Failures (CCF) are evaluated by beta-factor method. The reliability target for SGDHRS arrived from DHR reliability requirement and the ultimate number of demands per year (7/y) on SGDHRS is that the failure frequency should be <=1.4E-8/de. Since it is found from the analysis that the unreliability of SGDHRS with identical loops is 5.2E-6/de and dominated by leak rates of components like AHX, DHX and sodium dump and isolation valves, options with diversity measures in important components were studied. The failure probability of SGDHRS for a design consisting of 2 types of diverse loops (Diverse AHX, DHX and sodium dump and isolation valves) is 2.1E-8/de, which practically meets the reliability requirement.
|
|
| 7. |
- Arul, A.J., et al.
(författare)
-
The power law character of off-site power failures
- 2003
-
Ingår i: Annals of Nuclear Energy. - 0306-4549. ; 30:14, s. 1401-1408
-
Tidskriftsartikel (refereegranskat)abstract
- A study on the behavior of off-site AC power failure recovery times at three nuclear plant sites is presented. It is shown, that power law is appropriate for the representation of failure frequency–duration correlation function of off-site power failure events, based on simple assumptions about component failure and repair rates. It is also found that the annual maxima of power failure duration follow Frechet distribution, which is a type II asymptotic distribution, strengthening our assumption of power law for the parent distribution. The extreme value distributions obtained are used for extrapolation beyond the region of observation.
|
|
| 8. |
- Ashaduzzaman, M., et al.
(författare)
-
Studies on an on/off-switchable immunosensor for troponin T
- 2015
-
Ingår i: Biosensors & bioelectronics. - : Elsevier BV. - 0956-5663 .- 1873-4235. ; 73
-
Tidskriftsartikel (refereegranskat)abstract
- Regeneration is a key goal in the design of immunosensors. In this study, we report the temperature-regulated interaction of N-isopropylacrylamide (PNIPAAm) functionalised cardiac troponin T (cTnT) with anti-cTnT. Covalently bonded PNIPAAm on an anti-cTnT bioelectrode showed on/off-switchability, regeneration capacity and temperature triggered sensitivity for cTnT. Above the lower critical solution temperature (LCST), PNIPAAm provides a liphophilic microenvironment with specific volume reduction at the bioelectrode surface, making available binding space for cTnT, and facilitating analyte recognition. Computational studies provide details about the structural changes occurring at the electrode above and below the LCST. Furthermore, free energies associated with the binding of cTnT with PNIPAAm at 25 (δGcoil=-6.0Kcal/mole) and 37°C (δGglobular=-41.0kcal/mole) were calculated to elucidate the interaction and stability of the antigen-antibody complex. The responsiveness of such assemblies opens the way for miniaturised, smart immuno-technologies with 'built-in' programmable interactions of antigen-antibody upon receiving stimuli.
|
|
| 9. |
- Brown, Andrew S., et al.
(författare)
-
Sampling of gaseous sulfur-containing compounds at low concentrations with a review of best-practice methods for biogas and natural gas applications
- 2015
-
Ingår i: TrAC. Trends in analytical chemistry. - : Elsevier BV. - 0165-9936 .- 1879-3142. ; 64, s. 42-52
-
Tidskriftsartikel (refereegranskat)abstract
- The accurate quantification of low-concentration sulfur-containing compounds is essential for the biogas and natural gas industries. We review literature data for the stability of these compounds in standard gas mixtures when sampled in cylinders with different passivations, sample bags, sorbent tubes, solid-phase microextraction and glass sampling bulbs, and we present new data obtained at our three National Measurement Institutes. We show that losses of sulfur-containing compounds are minimized when using passivated sampling cylinders, and the most suitable sorbent material for sampling these compounds is Tenax TA. We also discuss methods for transferring gas from sample vessels to analyzers and give recommendations for the selection of regulators (and other pressure-reducing devices) and transfer lines. Further, we propose approaches that could be taken to reduce or correct for losses in order to provide more accurate measurements of sulfur-containing compounds.
|
|
| 10. |
- Low, Donald E., et al.
(författare)
-
Guidelines for Perioperative Care in Esophagectomy : Enhanced Recovery After Surgery (ERAS®) Society Recommendations
- 2019
-
Ingår i: World Journal of Surgery. - : Springer. - 0364-2313 .- 1432-2323. ; 43:2, s. 299-330
-
Forskningsöversikt (refereegranskat)abstract
- INTRODUCTION: Enhanced recovery after surgery (ERAS) programs provide a format for multidisciplinary care and has been shown to predictably improve short term outcomes associated with surgical procedures. Esophagectomy has historically been associated with significant levels of morbidity and mortality and as a result routine application and audit of ERAS guidelines specifically designed for esophageal resection has significant potential to improve outcomes associated with this complex procedure.METHODS: A team of international experts in the surgical management of esophageal cancer was assembled and the existing literature was identified and reviewed prior to the production of the guidelines. Well established procedure specific components of ERAS were reviewed and updated with changes relevant to esophagectomy. Procedure specific, operative and technical sections were produced utilizing the best current level of evidence. All sections were rated regarding the level of evidence and overall recommendation according to the evaluation (GRADE) system.RESULTS: Thirty-nine sections were ultimately produced and assessed for quality of evidence and recommendations. Some sections were completely new to ERAS programs due to the fact that esophagectomy is the first guideline with a thoracic component to the procedure.CONCLUSIONS: The current ERAS society guidelines should be reviewed and applied in all centers looking to improve outcomes and quality associated with esophageal resection.
|
|
