Oncogenic kinase inhibitors show short-lived responses in the clinic due to high rate of acquired resistance. We previously showed that pharmacologically exploiting oncogene-induced proteotoxic ...stress can be a viable alternative to oncogene-targeted therapy. Here, we performed extensive analyses of the transcriptomic, metabolomic and proteostatic perturbations during the course of treatment of Her2+ breast cancer cells with a Her2 inhibitor covering the drug response, resistance, relapse and drug withdrawal phases. We found that acute Her2 inhibition, in addition to blocking mitogenic signaling, leads to significant decline in the glucose uptake, and shutdown of glycolysis and of global protein synthesis. During prolonged therapy, compensatory overexpression of Her3 allows for the reactivation of mitogenic signaling pathways, but fails to re-engage the glucose uptake and glycolysis, resulting in proteotoxic ER stress, which maintains the protein synthesis block and growth inhibition. Her3-mediated cell proliferation under ER stress during prolonged Her2 inhibition is enabled due to the overexpression of the eIF2 phosphatase GADD34, which uncouples protein synthesis block from the ER stress response to allow for active cell growth. We show that this imbalance in the mitogenic and proteostatic signaling created during the acquired resistance to anti-Her2 therapy imposes a specific vulnerability to the inhibition of the endoplasmic reticulum quality control machinery. The latter is more pronounced in the drug withdrawal phase, where the de-inhibition of Her2 creates an acute surge in the downstream signaling pathways and exacerbates the proteostatic imbalance. Therefore, the acquired resistance mechanisms to oncogenic kinase inhibitors may create secondary vulnerabilities that could be exploited in the clinic.
The commercial processes to extract iron from ilmenite (FeTiO
3
) essentially include energy-intensive methods, such as high-temperature reduction smelting or preoxidation, coupled with reduction by ...carbon. However, due to altered mineralogy of ilmenite caused by weathering at sea coast, the reduction of iron remains incomplete in either of these processes, demanding a high concentration of acid when used for extraction of high-purity TiO
2
for high-end applications. We developed a process for the flux-catalyzed reduction of a partially weathered ilmenite ore of Indian origin. Initially, the effect of flux material and temperature was evaluated using thermogravimetric/diffraction thermal analysis (TG/DTA). The reduction behavior of the fluxed self-reducing pellets of ilmenite was then studied in a raising hearth furnace. The TG/DTA results indicated improved performance of sodium carbonate over lime within a temperature range of 1173 K to 1373 K. Under different reduction conditions in raising hearth furnace experiments, the leaching of reduced ilmenite in diluted hydrochloric acid (6.6 pct concentration) produced different grades of synthetic rutile. The best reduction conditions under optimized parameters enhanced the TiO
2
from initial 51 to 93 wt pct in the synthetic rutile. The X-ray diffraction and electron probe microanalysis investigation of the unreduced and reduced ilmenite revealed the conversion of the Fe
x
O
y
-SiO
2
-Al
2
O
3
system to Na
2
O-SiO
2
-Al
2
O
3
by sodium carbonate. The thermochemical analysis further explained the influence of sodium carbonate on the liquidus of Na
2
O-SiO
2
-Al
2
O
3
slag. The improved process enables the complete reduction of the iron from weathered ilmenite to produce a high-grade rutile.
Sustainable fuel for the transportation sector Agrawal, Rakesh; Singh, Navneet R; Ribeiro, Fabio H ...
Proceedings of the National Academy of Sciences - PNAS,
03/2007, Letnik:
104, Številka:
12
Journal Article
Recenzirano
Odprti dostop
A hybrid hydrogen-carbon (H₂CAR) process for the production of liquid hydrocarbon fuels is proposed wherein biomass is the carbon source and hydrogen is supplied from carbon-free energy. To implement ...this concept, a process has been designed to co-feed a biomass gasifier with H₂ and CO₂ recycled from the H₂-CO to liquid conversion reactor. Modeling of this biomass to liquids process has identified several major advantages of the H₂CAR process. (i) The land area needed to grow the biomass is <40% of that needed by other routes that solely use biomass to support the entire transportation sector. (ii) Whereas the literature estimates known processes to be able to produce almost equal to30% of the United States transportation fuel from the annual biomass of 1.366 billion tons, the H₂CAR process shows the potential to supply the entire United States transportation sector from that quantity of biomass. (iii) The synthesized liquid provides H₂ storage in an open loop system. (iv) Reduction to practice of the H₂CAR route has the potential to provide the transportation sector for the foreseeable future, using the existing infrastructure. The rationale of using H₂ in the H₂CAR process is explained by the significantly higher annualized average solar energy conversion efficiency for hydrogen generation versus that for biomass growth. For coal to liquids, the advantage of H₂CAR is that there is no additional CO₂ release to the atmosphere due to the replacement of petroleum with coal, thus eliminating the need to sequester CO₂.
To provide evidence-based recommendations updating the 2020 ASCO and Ontario Health (Cancer Care Ontario) guideline on systemic therapy for patients with stage IV non-small-cell lung cancer without ...driver alterations.
ASCO updated recommendations on the basis of an ongoing systematic review of randomized clinical trials from 2018 to 2021.
This guideline update reflects changes in evidence since the previous update. Five randomized clinical trials provide the evidence base. Outcomes of interest include efficacy and safety.
In addition to 2020 options for patients with high programmed death ligand-1 (PD-L1) expression (tumor proportion score TPS ≥ 50%), nonsquamous cell carcinoma (non-SCC), and performance status (PS) 0-1, clinicians may offer single-agent atezolizumab. With high PD-L1 expression (TPS ≥ 50%), non-SCC, and PS 0-1, clinicians may offer nivolumab and ipilumumab alone or nivolumab and ipilimumab plus chemotherapy. With negative (0%) and low positive PD-L1 expression (TPS 1%-49%), non-SCC, and PS 0-1, clinicians may offer nivolumab and ipilimumab alone or nivolumab and ipilimumab plus chemotherapy. With high PD-L1 expression, SCC, and PS 0-1, clinicians may offer single-agent atezolizumab. With high PD-L1 expression, squamous cell carcinoma (SCC), and PS 0-1, clinicians may offer nivolumab and ipilimumab alone or in combination with two cycles of platinum-based chemotherapy. With negative and low positive PD-L1 expression, SCC, and PS 0-1, clinicians may offer nivolumab and ipilimumab alone or in combination with two cycles of platinum-based chemotherapy. With non-SCC who received an immune checkpoint inhibitor and chemotherapy as first-line therapy, clinicians may offer second-line paclitaxel plus bevacizumab. With non-SCC, who received chemotherapy with or without bevacizumab and immune checkpoint inhibitor therapy, clinicians should offer the options of third-line single-agent pemetrexed, docetaxel, or paclitaxel plus bevacizumab.Additional information is available at www.asco.org/thoracic-cancer-guidelines.
Abstract The present study investigated the relationship between MSH3 and MSH6 genes in lung cancer patients. Genotyping of lung cancer patients and healthy controls was performed. Odds ratio values ...were calculated and survival analysis performed. Patients with mutant genotype (TT) for MSH6 polymorphism have 1.5-fold risk for the development of lung cancer ( p = 0.03). For non-smokers, the mutant-type genotype had a threefold increased risk of lung cancer ( p = 0.01). Patients administered with docetaxel and carbo/cisplatin and carrying GT genotype for MSH6 polymorphism, patients reported a decrease in median survival time (4.9 vs 9.13 months). MSH3 and MSH6 polymorphisms are involved in modulating the risk towards lung cancer. MSH6 polymorphism is associated with high mortality rate for patients undergoing cisplatin and docetaxel chemotherapy.
Non-small cell lung cancer comprises 85% of the global lung cancer cases. Conventional chemotherapeutics possess certain limitations like systemic toxicity and drug resistance that requires the ...development of new therapeutic agents for successful treatment of lung cancer. Actinonin, a human peptide deformylase inhibitor, has demonstrated anti-cancerous properties in various leukemias and solid cancer types. However, it has limited therapeutic application because of its low bioavailability and systemic toxicity if administered in free form. This limitation can be overcome by using nano-delivery systems that will increase the therapeutic efficacy of actinonin. In the present study, human serum albumin actinonin nanoparticles were prepared using a desolvation technique and folic acid was conjugated to lysine residues of albumin for effective delivery to the lung. The lung adenocarcinoma model was established 24 weeks after intraperitoneal administration of urethane and chemotherapeutic efficacy of free as well as nanoencapsulated actinonin was evaluated. This study demonstrated anti-proliferative potential of folic acid conjugated human serum albumin nanoparticles encapsulating actinonin. The intraperitoneally administered nanoformulation exhibited sustain release profile of actinonin with longer half-life and mean retention time. The reduced dose frequency resulted in therapeutic efficacy comparable to free drug in vivo in terms of 100% survival and reduced tumor burden along with downregulation of epidermal growth factor receptor, folate receptor α and peptide deformylase expression in lung adenocarcinoma mice model. Therefore, actinonin encapsulated albumin nanoparticles-based therapy holds great potential as an alternative strategy to improve its anti-cancerous activity against lung adenocarcinoma.
This study presents a systems approach for comparing alternative routes for converting CO2 to liquid fuel using solar energy based on a novel metric of sun-to-fuel (STF) efficiency. The metric refers ...to the fraction of incident solar energy that is recovered in the liquid fuel. The STF efficiency analysis identifies energy and land use efficient routes that require immediate research and development effort to speed up their progress toward long-term cost-effectiveness. The analysis’ unique insights are particularly relevant for densely populated regions, having scarce per capita land availability relative to the per capita energy demands. With atmospheric CO2 as the renewable carbon source, we present a detailed case study comparing the currently known photosynthetic routes with a theoretical route based on direct extraction of CO2 from air and its subsequent thermochemical conversion to liquid fuel. The findings indicate that the latter route could be potentially more energy and thereby land use efficient than any of the currently known photosynthetic routes, therefore, warranting its inclusion in any transportation fuels research portfolio. An interesting finding of our study is that for the interim period while CO2 extraction is still uneconomical and CO2 sourced from power plants is instead used, the relative energy efficiency of different routes remains unchanged. This suggests that the results in general are independent of the concentration of the CO2 source.
Majority of the pollination related studies are based on the diurnal pollinators, and the nocturnal pollinators received less scientific attention. We reveal the significance of settling moths in ...pollination of angiosperm families in Himalayan ecosystem of North-East India. The refined and novel method of pollen extraction from the proboscides provides a more robust assessment of the pollen carrying capacity. The study is based on one of the largest data sets (140 pollen transporter moth species (PTMS)), with interpretation based on seasonal as well as altitudinal data. In the present study about 65% moths (91 species) carried sufficient quantities of pollen grains to be considered as potential pollinators (PPMS). Teliphasa sp. (Crambidae) and Cuculia sp. (Noctuidae) are found to carry the highest quantity of pollen. We found pollen grains of 21 plant families and the abundant pollen are from Betulaceae, Fabaceae, Rosaceae and Ericaceae. Species composition of PTMS and PPMS in pre-monsoon, monsoon, and post-monsoon revealed the dominance of Geometridae. Maximum diversity of PTMS and PPMS is found from 2000 to 2500 m altitude. The nocturnal pollen transfer network matrices exhibited high degree of selectivity (H
' = 0.86).
ObjectivesTo evaluate the importance of the frequency and duration of lifestyle interventions for achieving weight loss over ≥1 year and associations with all-cause mortality.DesignMeta-analysis of ...randomised trials using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and RevMan software version 5·2 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen).Data sourcesMEDLINE, CENTRAL, Google and Science Direct databases alongside reference lists of appropriate articles and meta-analyses.Eligibility criteriaRandomised studies published in English-language journals from 1980 to June 2018 that assessed lifestyle compared with control interventions on weight loss and that included ≥100 subjects and reported weight change and mortality for ≥1 year.Data extraction and synthesisTwo independent reviewers extracted data and assessed risk of bias. Data were pooled using the generic inverse-variance method and expressed as mean differences (MDs) with 95% CI and OR with 95% CI as appropriate. Heterogeneity was assessed (Cochran Q statistic) and quantified (I2 statistic). The Grading of Recommendations Assessment, Development, and Evaluation score was used to assess the certainty of the evidence.Results31 randomised trials with a total of 20 816 overweight or obese participants were included. 70% of participants had cardiometabolic risk factors. Body weight was lower for lifestyle intervention compared with the control at 1 year (3.63 kg, 95% CI 2.58 to 4.67) and at 3 years (2.45 kg, 95% CI 1.17 to 3.73). Weight loss at 1 year was greater in studies with >28 compared with ≤28 interventions per year (4.50 kg, 95% CI 3.03, 5.97 vs 2.38, 95% CI 0.78 to 3.98 kg, p=0.001). In all studies, there were 593 deaths (~0.3%/year). The ORs for mortality for weight loss interventions compared with the controls was 0.86 (95% CI 0.73 to 1.02), p=0.09.ConclusionIn predominantly healthy populations with risk factors, there is a dose response with number of lifestyle interventions and weight loss. Frequent and sustained interventions are needed to achieve a clinically significant 5% weight loss. There was insufficient evidence to reliably evaluate the benefits in persons with known cardiovascular disease or cancer.Trial registration numberCRD42018095067.
The current study investigates the thermo-physical properties of the Mg-based hybrid composite produced via hot press sintering. The
Al
2
O
3
Al
2
O
3
SiC and Al
2
O
3
particulates were selected as ...reinforcement in the Mg matrix. The volume fraction of the matrix and the reinforcements is kept constant at 40:60. However, by varying the volume fraction ratio of SiC and Al
2
O
3
five different composites were prepared, designated as Mg–10SiC50Al
2
O
3
, Mg–20SiC40Al
2
O
3
, Mg–30SiC30Al
2
O
3
, Mg–40SiC20Al
2
O
3
and Mg–50SiC10Al
2
O
3
. The effect of SiC and Al
2
O
3
reinforcement on thermal conductivity, specific heat capacity and density were evaluated. XRD analysis determined the formation of intermittent phases like Mg
2
Si and MgO in the Mg matrix composite, whereas SEM analysis confirmed an almost uniform distribution of the reinforcements in the Mg matrix. Among the developed composites, the highest thermal conductivity of 193.42 W/mK (for Mg–50SiC10Al
2
O
3
) and highest specific heat of 4.68 kJ/kg°C (for Mg–30SiC30Al
2
O
3
) were observed along with the relative density of 85–77%. The properties achieved by the developed composites are found to be aligned with the requirement of third-generation solar energy storage materials and could be used for thermal storage usage such as solar thermal applications.
PDF
