There are considerable challenges in directly targeting the mutant p53 protein, given the large heterogeneity of p53 mutations in the clinic. An alternative approach is to exploit the altered fitness ...of cells imposed by loss-of-wild-type p53. Here we identify niclosamide through a HTS screen for compounds selectively killing p53-deficient cells. Niclosamide impairs the growth of p53-deficient cells and of p53 mutant patient-derived ovarian xenografts. Metabolome profiling reveals that niclosamide induces mitochondrial uncoupling, which renders mutant p53 cells susceptible to mitochondrial-dependent apoptosis through preferential accumulation of arachidonic acid (AA), and represents a first-in-class inhibitor of p53 mutant tumors. Wild-type p53 evades the cytotoxicity by promoting the transcriptional induction of two key lipid oxygenation genes, ALOX5 and ALOX12B, which catalyzes the dioxygenation and breakdown of AA. Therefore, we propose a new paradigm for targeting cancers defective in the p53 pathway, by exploiting their vulnerability to niclosamide-induced mitochondrial uncoupling.
The efficacy and safety of vitamin K antagonists for the prevention of thromboembolism are dependent on the time for which the International Normalized Ratio (INR) is in the therapeutic range. The ...objective of our study was to determine the effect of introducing a simple two-step dosing algorithm, as compared with dosing by anticoagulation clinic staffs on the basis of their experience, on time in therapeutic range (TTR) of warfarin therapy.
We compared TTRs of all clinic patients before and after the introduction of a simple two-step dosing algorithm at a single anticoagulation clinic in Canada, between 1 August 2006 and 24 December 2008. TTR was calculated using the linear interpolation method of Rosendaal.
We included 873 patients in the 'before' phase and 1088 patients in the 'after' phase. Introduction of the dosing algorithm significantly increased TTR of patients with a therapeutic INR range of 2-3 from 67.2% to 73.2% (P < 0.001), and that of patients with a therapeutic INR range of 2.5-3.5 from 49.8% to 63.8% (P < 0.001).
The introduction of a simple two-step warfarin-dosing algorithm in place of dosing by experienced anticoagulation clinic staff significantly improved mean TTR for patients in a tertiary-care anticoagulation clinic. This inexpensive and widely applicable algorithm has the potential to improve warfarin control.
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by restrictive behaviour, deficit in social skills and interaction. The multifactorial etiology, complex ...pathophysiology and different combination of symptoms (unusual speech patterns, frequent repetition of phrases) make it difficult to treat. Thus, present study aimed to find the protective effects of oxiracetam alone and in combination with zinc on brain behavioral, biochemical, pro-inflammatory cytokines and neurotransmitters level. Rats were administered with propionic acid (250 mg/kg p.o.) for 3 days and immediately on next day treatment were given with oxiracetam (25, 50 mg/kg i.p), zinc (4 mg/kg) as well as oxiracetam (25 mg/kg i.p) in combination with zinc (4 mg/kg p.o). Behavioral parameters were performed from 22th to 28th day. On 29th day, all the animals were sacrificed by cervical dislocation and the brain was preserved for biochemical (LPO, GSH, nitrite, mitochondrial complex I, IV and cAMP), neuroinflammatory (TNF-α, IL-1β, IL-6) and neurotransmitters (5-HT, GABA, glutamate and acetylcholine) analysis. The propionic acid administration showed memory impairment, restrictive behavior, increased proinflammatory cytokines level, biochemical and neurotransmitters alteration. However, treatment with oxiracetam alone and in combination with zinc significantly attenuated behavioral, biochemical, inflammatory cytokines and restored neurotransmitters level. The finding of present study demonstrated that oxiracetam alone and in combination with zinc afforded superior anti-autistic effect through antioxidant, anti-inflammatory and anti-excitotoxic mechanisms and could serve as attractive strategy in managing autism.
High temperature during reproduction is a major factor limiting the yield of chickpea (Cicer arietinum L.). Observations in the field from late season experiments (February–May) and various high ...temperature regimes generated in controlled environments showed clear genetic variation in male reproductive tissue (anther and pollen), its function (pollen germination and tube growth) and pod set. Greater pod setting ability of heat tolerant genotypes (ICC 1205 and ICC 15614) compared to heat sensitive genotypes (ICC 4567 and ICC 10685) was observed in both the field and controlled conditions. Both anthers and pollen showed more structural abnormalities under stress such as changes in anther locule number, anther epidermis wall thickening and pollen sterility, rather than function (e.g. in vivo pollen tube growth). The critical temperature for pod set was ≥37°C in heat tolerant genotypes (ICC 1205 and ICC 15614) and ≥33°C for heat sensitive genotypes (ICC 4567 and ICC 10685). Overall, pod set showed greater sensitivity in the controlled environments where a 67% reduction was observed at ≥34/19°C compared to the control (27/16°C). In the field, a pod set reduction of more than 50% occurred at high ambient day temperature (36°C) and the stigma was still receptive at 40.2/25.5°C. In contrast, under controlled conditions the stigma was still receptive at 35/20°C in four genotypes. Clearly, chickpea pollen grains are more sensitive to high temperature than the stigma in both the field and controlled environments. Among the four genotypes tested, ICC 1205 was the most heat tolerant and ICC 4567 was the most heat sensitive.
Abstract Recycled Aggregate (RA) reduces the carbon footprint and disposal problem associated with construction and demolition debris. As India is a lower middle country, demolition of existing ...buildings and constructions is taking place at a rapid pace. According to the Building Materials Promotion Board, India generates 150 million tons of construction and demolition waste annually. A study commissioned by the BBMP estimated CDW generation in Bengaluru 2,500 to 3,000 tons per day in 2022, leading to the problem of CDW disposal. The biggest environmental problem is the rapid manufacture of cement for construction activities, which generates millions of tons of carbon dioxide annually, the greatest environmental concern. Coarse aggregate was made from demolished buildings and other construction debris. The construction and demolition were collected from C&D Waste Traders, sirjala Bengaluru of 10 mm size recycled aggregate using. As the crushed aggregate is porous in nature due to residual slurry, these aggregates were treated in two stages: abrasion to remove residual loose slurry, and then again by immersing the aggregate in fly ash solution of concentration 1:6. Additionally, these cured aggregates are mixed with a strong geopolymer precursor in a mix ratio of 1:4:5 to form 400X200X150 mm block. To evaluate the masonry behavior of concrete blocks the tests are conducted as per the ASTM codes. The Prism Test on Masonry was conducted as per the code ASTM C 1314 and Diagonal Tension (Shear) in Masonry Assemblages as per the code ASTM E519 and this experimental study is compared with the ANSYS Software.
Varying the Al content, strongly influences the microstructure, magnetic and microhardness of additively manufactured Alx(CoFeNi) (x = 0, 10, 30) complex concentrated alloys (CCA). Compared to the ...single FCC phase of CoFeNi, the hierarchical FCC/L12+BCC/B2 heterostructure of heat treated Al10(CoFeNi) CCA displayed substantially improved saturation magnetization, Curie temperature and microhardness. However, there was no significant change in the properties of heat treated CoFeNi and Al30(CoFeNi) CCA. These findings can be rationalized via thermodynamic modelling of the phase stability. We have demonstrated the feasibility of exploiting additive manufacturing for rapidly screening and developing novel high-performance alloys for next generation rotating electrical machines.
Display omitted
An elegant synthetic strategy was adopted for the preparation of N‐triazolo methyl substituted fluoroquinolones 4 and screened for their antimicrobial activity. The synthetic methodology starts from ...N‐propargylation of ethyl 7‐chloro‐6‐fluoro‐4‐hydroxyquinoline‐3‐carboxylate (1) followed by reaction with azides through click reaction under Sharpless conditions furnished triazole substituted quinolone ester 3. The latter quinolone esters were reacted with various secondary amines to furnish the corresponding quinolone derivatives 4. Alternatively, quinolone carboxylic derivatives 7a, 7b, 7c, 7d were prepared in two steps from triazole tagged quinolone ester. All the final products were screened against various bacterial and fungal strains. Compounds 4a, 4b, 4c and 4k showed moderate antibacterial activity, and 4f showed promising activity against fungal strains.
PDF
