The tumour suppressor p53 is the most frequently mutated gene in human cancer, with more than half of all human tumours carrying mutations in this particular gene. Intense efforts to develop drugs ...that could activate or restore the p53 pathway have now reached clinical trials. The first clinical results with inhibitors of MDM2, a negative regulator of p53, have shown efficacy but hint at on-target toxicities. Here, we describe the current state of the development of p53 pathway modulators and new pathway targets that have emerged. The challenge of targeting protein-protein interactions and a fragile mutant transcription factor has stimulated many exciting new approaches to drug discovery.
The opto-thermal properties of Au- and Ag-coated core–shell hybrid nanoparticles (NPs) have been thoroughly investigated by using the PyMieLab V1.0 simulation tool based on electrodynamics modelling. ...We, specifically, investigated the plasmonic resonance tunability and spatial temperature profiles of Au- and Ag-coated composed hybrid core–shell nanospheres as optimized combinations of alloy core (viz. Au
0.25
Ag
0.75
, Au
0.25
Cu
0.75
, Au
0.75
Al
0.25
, Ag
0.75
Cu
0.25
and Ag
0.75
Al
0.25
) immersed in the local water (
n
= 1.33) media. In the present core–shell nanostructure configuration, the alloy core radius (
r
) has been changed from 5 to 50 nm (with 5-nm step-size) and shell thickness,
t
=
5
,
and
10
nm
is kept the same with varying core radii. The localized surface plasmon resonance (LSPR) of Au- and Ag-coated optimized alloys composed of hybrid core–shell nanospheres is tuned between 238–545 nm and 347–531 nm, respectively, and lies under the ultraviolet–visible segment of the electromagnetic band. The temperature recorded at the surface of core–shell NPs (i.e. alloy core@gold/silver shell) lies between the range of 0.20 and 2.38 °C (for Au-coated alloys) and 0.64–2.44 °C (for Ag-coated alloy) with different core/shell size ratios. The present results are of paramount importance for using these alloy core–plasmonic shell NPs in several types of thermoplasmonic applications.
Graphical Abstract
Aims
This study was conducted to investigate indigenous seed endophyte effects on browntop millet seedling development. We report that seed‐inhabiting bacterial endophytes are responsible for ...promoting seedling development, including stimulation of root hair formation, increasing root and shoot length growth and increasing photosynthetic pigment content of seedlings. Bacterial endophytes also improved resistance of seedlings to disease.
Methods and Results
A total of four endophytic bacteria were isolated from surface‐sterilized seeds and identified by 16S rDNA sequencing as Curtobacterium sp. (M1), Microbacterium sp. (M2), Methylobacterium sp. (M3) and Bacillus amyloliquefaciens (M4). Removal of bacteria with streptomycin treatment from the seeds compromised seedling growth and development. When endophytes were reinoculated onto seeds, seedlings recovered normal development. Strains M3 and M4 were found to be most potent in promoting growth of seedlings. Bacteria were found to produce auxin, solubilize phosphate and inhibit fungal pathogens. Significant protection of seedlings from Fusarium infection was found using strain M4 in microcosm assays. The antifungal lipopeptide genes for surfactin and iturin were detected in M4; culture extracts of M4 showed a positive drop collapse result for surfactins.
Conclusions
This study demonstrates that browntop millet seeds vector indigenous endophytes that are responsible for modulation of seedling development and protection of seedlings from fungal disease.
Significance and Impact of the Study
This study is significant and original in that it is the first report of seed‐inhabiting endophytes of browntop millet that influence seedling development and function in defence against soilborne pathogens. This study suggests that conservation and management of seed‐vectored endophytes may be important in development of more sustainable agricultural practices.
In comparison to single Noble metal nanoparticles (NPs), bimetallic nanoparticles allow fine-tuning of the optical and photothermal properties. Considering the fact that both Au and Ag plasmonic NPs ...exhibit strong and enhanced optical absorption in the visible spectrum, the composition of these two materials is notably intriguing. Therefore, the combination of these two metals as an alloy of Au
x
–Ag
(1−x)
will provide better control of optical and thermoplasmonic properties by changing the size and composition. The proposed computer simulation work examines the thermal effects of Au–Ag alloy nanospheres under surface plasmon resonance (SPR) due to the coherent oscillation of conduction electrons within the NPs. It is demonstrated that the SPR of Au
x
–Ag
(1−x)
alloy nanospheres could be easily altered by varying the radius and also the composition of alloys (in water ambience). The rise of steady-state temperature is calculated by the integration of Ag into spherical Au NPs, as demonstrated by photothermal heat transfer research. Absorption of light by metallic alloy nanospheres was studied by changing the composition of such alloy spheres with a possibility to alter the SPR absorption range, which is tuned from 392 to 580 nm. This investigation of the optical and photothermal properties of bimetallic Au–Ag alloy nanospheres offers a thorough scientific understanding towards the synthesis of new custom plasmonic nanostructured materials.
Graphical abstract
Schematic of the photo-thermal conversion process in spherical NPs along with its temperature profile.
The performance of Stirling engines meets the demands of the efficient use of energy and environmental security and therefore they are the subject of much current interest. Hence, the development and ...investigation of Stirling engine have come to the attention of many scientific institutes and commercial companies. The Stirling engine is both practically and theoretically a significant device, its practical virtue is simple, reliable and safe which was recognized for a full century following its invention by Robert Stirling in 1816. The engine operates on a closed thermodynamic cycle, which is reversible. Today Stirling cycle-based systems are in commercial use as a heat pump, cryogenic refrigeration and air liquefaction. As a prime mover, Stirling cycles remain the subject of research and development efforts. The objective of this paper is to provide fundamental information and present a detailed review of the past efforts taken for the development of the Stirling cycle engine and techniques used for engine analysis. A number of attempts have been made by researches to build and improve the performance of Stirling engines. It is seen that for successful operation of engine system with good efficiency a careful design of heat exchangers, proper selection of drive mechanism and engine configuration is essential. The study indicates that a Stirling cycle engine working with relatively low temperature with air of helium as working fluid is potentially attractive engines of the future, especially solar-powered low-temperature differential Stirling engines with vertical, double acting, and gamma configuration.
The phase III MONALEESA-2 study demonstrated significantly prolonged progression-free survival (PFS) and a manageable toxicity profile for first-line ribociclib plus letrozole versus placebo plus ...letrozole in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer. Here, we report updated efficacy and safety data, together with exploratory biomarker analyses, from the MONALEESA-2 study.
A total of 668 postmenopausal women with HR+, HER2– recurrent/metastatic breast cancer were randomized (1 : 1; stratified by presence/absence of liver and/or lung metastases) to ribociclib (600mg/day; 3-weeks-on/1-week-off; 28-day treatment cycles) plus letrozole (2.5mg/day; continuous) or placebo plus letrozole. The primary end point was locally assessed PFS. The key secondary end point was overall survival (OS). Other secondary end points included overall response rate (ORR) and safety. Biomarker analysis was an exploratory end point.
At the time of the second interim analysis, the median duration of follow-up was 26.4months. Median PFS was 25.3months 95% confidence interval (CI) 23.0–30.3 for ribociclib plus letrozole and 16.0months (95% CI 13.4–18.2) for placebo plus letrozole (hazard ratio 0.568; 95% CI 0.457–0.704; log-rank P=9.63×10−8). Ribociclib treatment benefit was maintained irrespective of PIK3CA or TP53 mutation status, total Rb, Ki67, or p16 protein expression, and CDKN2A, CCND1, or ESR1 mRNA levels. Ribociclib benefit was more pronounced in patients with wild-type versus altered receptor tyrosine kinase genes. OS data remain immature, with 116 deaths observed; 50 in the ribociclib arm and 66 in the placebo arm (hazard ratio 0.746; 95% CI 0.517–1.078). The ORR was 42.5% versus 28.7% for all patients treated with ribociclib plus letrozole versus placebo plus letrozole, respectively, and 54.5% versus 38.8%, respectively, for patients with measurable disease. Safety results, after a further 11.1months of follow-up, were comparable with those reported at the first analysis, with no new or unexpected toxicities observed, and no evidence of cumulative toxicity.
The improved efficacy outcomes and manageable tolerability observed with first-line ribociclib plus letrozole are maintained with longer follow-up, relative to letrozole monotherapy.
NCT01958021
Dimension preserving approximation Verma, S.; Massopust, P. R.
Aequationes mathematicae,
12/2022, Letnik:
96, Številka:
6
Journal Article
Recenzirano
Odprti dostop
This article introduces the novel notion of dimension preserving approximation for continuous functions defined on 0, 1 and initiates the study of it. Restrictions and extensions of continuous ...functions in regards to fractal dimensions are also investigated.
A
bstract
Non-Riemannian gravitational theories suggest alternative avenues to understand properties of quantum gravity and provide a concrete setting to study condensed matter systems with ...non-relativistic symmetry. Derivation of an action principle for these theories generally proved challenging for various reasons. In this technical note, we employ the formulation of double field theory to construct actions for a variety of such theories. This formulation helps removing ambiguities in the corresponding equations of motion. In particular, we embed Torsional Newton-Cartan gravity, Carrollian gravity and String Newton-Cartan gravity in double field theory, derive their actions and compare with the previously obtained results in literature.
Chemotherapy, radiation, and surgery are the conventional treatment modalities for cancer. The success achieved with these approaches has been limited due to several factors like chemoresistance to ...drugs, non‐specificity leading to peripheral toxicity, and non‐resectable tumors. To combat these problems, the concept of targeted therapy using immunotoxins was developed. Immunotoxins are chimeric proteins with a cell‐selective ligand chemically linked or genetically fused to a toxin moiety and can target cancer cells overexpressing tumor‐associated antigens, membrane receptors, or carbohydrate antigens. Ligands for these receptors or monoclonal antibodies or single chain variable fragments directed against these antigens are fused with bacterial or plant toxins and are made use of as immunotoxins. Pseudomonas exotoxin, anthrax toxin, and diphtheria toxin are the commonly used bacterial toxins. Ricin, saporin, gelonin, and poke weed antiviral protein are the plant toxins utilized in immunotoxin constructs. Several such fusion proteins are in clinical trials, and denileukin difitox is a FDA‐approved fusion protein. In spite of the promise shown by bacterial‐ and plant toxin‐based chimeric proteins, their clinical application is hampered by several factors like immunogenicity of the toxin moiety and non‐specific toxicity leading to vascular leak syndrome. In order to overcome these problems, a novel generation of immunotoxins in which the cytotoxic moiety is an endogenous protein of human origin like proapoptotic protein or RNase has been developed. This review summarizes the advances in this new class of fusion protein and the future directions to be explored. (Cancer Sci 2009)
Drug-induced liver injury (DILI) is increasingly being recognised as a significant cause of both acute and chronic liver disease. The most commonly implicated agents are paracetamol, antimicrobials, ...non-steroidal anti-inflammatory drugs, statins, isoniazid and herbal remedies. Drug-induced hepatotoxicity is generally idiosyncratic in nature. The pathogenesis of DILI remains enigmatic, but involves exposure to the toxic agent, mitochondrial injury, failure of adaptation, and innate and adaptive immune responses. Diagnosis of drug-induced liver diseases can be difficult, but the key to causality is to diligently exclude other causes of liver injury, and to identify a characteristic clinical drug-related signature. Management of drug-induced liver injury is symptomatic, with early referral to a liver transplant unit at the first hint of liver failure, especially in those with non-paracetamol-induced liver injury. Prevention of drug hepatotoxicity includes increased vigilance during pre-clinical drug development and clinical trials, alanine aminotransferase monitoring with certain drugs, better marketing strategies, and the future identification of both diagnostic and prognostic biomarkers.
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