Polyphenols Sensitization Potentiates Susceptibility of MCF-7 and MDA MB-231 Cells to Centchroman

Polyphenols as “sensitizers” together with cytotoxic drugs as “inducers” cooperate to trigger apoptosis in various cancer cells. Hence, their combination having similar mode of mechanism may be a novel approach to enhance the efficacy of inducers. Additionally, this will also enable to achieve the physiological concentrations facilitating significant increase in the activity at concentrations which the compound can individually provide. Here we propose that polyphenols (Resveratrol (RES) and Curcumin (CUR)) pre-treatment may sensitize MCF-7/MDA MB-231 (Human Breast Cancer Cells, HBCCs) to Centchroman (CC, antineoplastic agent). 6 h pre-treated cells with 10 µM RES/CUR and 100 µM RES/30 µM CUR doses, followed by 10 µM CC for 18 h were investigated for Ser-167 ER-phosphorylation, cell cycle arrest, redox homeostasis, stress activated protein kinase (SAPKs: JNK and p38 MAPK) pathways and downstream apoptosis effectors. Low dose RES/CUR enhances the CC action through ROS mediated JNK/p38 as well as mitochondrial pathway in MCF-7 cells. However, RES/CUR sensitization enhanced apoptosis in p53 mutant MDA MB-231 cells without/with involvement of ROS mediated JNK/p38 adjunct to Caspase-9. Contrarily, through high dose sensitization in CC treated cells, the parameters remained unaltered as in polyphenols alone. We conclude that differential sensitization of HBCCs with low dose polyphenol augments apoptotic efficacy of CC. This may offer a novel approach to achieve enhanced action of CC with concomitant reduction of side effects enabling improved management of hormone-dependent breast cancer

Novel Gemcitabine Conjugated Albumin Nanoparticles: a Potential Strategy to Enhance Drug Efficacy in Pancreatic Cancer Treatment

Purpose: The present study reports a novel conjugate of gemcitabine (GEM) with bovine serum albumin (BSA) and thereof nanoparticles (GEM-BSA NPs) to potentiate the therapeutic efficacy by altering physicochemical properties, improving cellular uptake and stability of GEM. Methods: The synthesized GEM-BSA conjugate was extensively characterized by NMR, FTIR, MALDI-TOF and elemental analysis. Conjugation mediated changes in structural conformation and physicochemical properties were analysed by fluorescence, Raman and CD spectroscopy, DSC and contact angle analysis. Further, BSA nanoparticles were developed from BSA-GEM conjugate and extensively evaluated against in-vitro pancreatic cancer cell lines to explore cellular uptake pathways and therapeutic efficacy. Results: Various characterization techniques confirmed covalent conjugation of GEM with BSA. GEM-BSA conjugate was then transformed into NPs via high pressure homogenization technique with particle size 147.2 ± 7.3, PDI 0.16 ± 0.06 and ZP -19.2 ± 1.4. The morphological analysis by SEM and AFM revealed the formation of smooth surface spherical nanoparticles. Cellular uptake studies in MIA PaCa-2 (GEM sensitive) and PANC-1 (GEM resistant) pancreatic cell lines confirmed energy dependent clathrin internalization/endocytosis as a primary mechanism of NPs uptake. In-vitro cytotoxicity studies confirmed the hNTs independent transport of GEM in MIA PaCa-2 and PANC-1 cells. Moreover, DNA damage and annexin-V assay revealed significantly higher apoptosis level in case of cells treated with GEM-BSA NPs as compared to free GEM. Conclusions: GEM-BSA NPs were found to potentiate the therapeutic efficacy by altering physicochemical properties, improving cellular uptake and stability of GEM and thus demonstrated promising therapeutic potential over free drug

Identifying associations between diabetes and acute respiratory distress syndrome in patients with acute hypoxemic respiratory failure: an analysis of the LUNG SAFE database

Background: Diabetes mellitus is a common co-existing disease in the critically ill. Diabetes mellitus may reduce the risk of acute respiratory distress syndrome (ARDS), but data from previous studies are conflicting. The objective of this study was to evaluate associations between pre-existing diabetes mellitus and ARDS in critically ill patients with acute hypoxemic respiratory failure (AHRF). Methods: An ancillary analysis of a global, multi-centre prospective observational study (LUNG SAFE) was undertaken. LUNG SAFE evaluated all patients admitted to an intensive care unit (ICU) over a 4-week period, that required mechanical ventilation and met AHRF criteria. Patients who had their AHRF fully explained by cardiac failure were excluded. Important clinical characteristics were included in a stepwise selection approach (forward and backward selection combined with a significance level of 0.05) to identify a set of independent variables associated with having ARDS at any time, developing ARDS (defined as ARDS occurring after day 2 from meeting AHRF criteria) and with hospital mortality. Furthermore, propensity score analysis was undertaken to account for the differences in baseline characteristics between patients with and without diabetes mellitus, and the association between diabetes mellitus and outcomes of interest was assessed on matched samples. Results: Of the 4107 patients with AHRF included in this study, 3022 (73.6%) patients fulfilled ARDS criteria at admission or developed ARDS during their ICU stay. Diabetes mellitus was a pre-existing co-morbidity in 913 patients (22.2% of patients with AHRF). In multivariable analysis, there was no association between diabetes mellitus and having ARDS (OR 0.93 (0.78-1.11); p = 0.39), developing ARDS late (OR 0.79 (0.54-1.15); p = 0.22), or hospital mortality in patients with ARDS (1.15 (0.93-1.42); p = 0.19). In a matched sample of patients, there was no association between diabetes mellitus and outcomes of interest. Conclusions: In a large, global observational study of patients with AHRF, no association was found between diabetes mellitus and having ARDS, developing ARDS, or outcomes from ARDS. Trial registration: NCT02010073. Registered on 12 December 2013

Spontaneous Breathing in Early Acute Respiratory Distress Syndrome: Insights From the Large Observational Study to UNderstand the Global Impact of Severe Acute Respiratory FailurE Study

OBJECTIVES: To describe the characteristics and outcomes of patients with acute respiratory distress syndrome with or without spontaneous breathing and to investigate whether the effects of spontaneous breathing on outcome depend on acute respiratory distress syndrome severity. DESIGN: Planned secondary analysis of a prospective, observational, multicentre cohort study. SETTING: International sample of 459 ICUs from 50 countries. PATIENTS: Patients with acute respiratory distress syndrome and at least 2 days of invasive mechanical ventilation and available data for the mode of mechanical ventilation and respiratory rate for the 2 first days. INTERVENTIONS: Analysis of patients with and without spontaneous breathing, defined by the mode of mechanical ventilation and by actual respiratory rate compared with set respiratory rate during the first 48 hours of mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: Spontaneous breathing was present in 67% of patients with mild acute respiratory distress syndrome, 58% of patients with moderate acute respiratory distress syndrome, and 46% of patients with severe acute respiratory distress syndrome. Patients with spontaneous breathing were older and had lower acute respiratory distress syndrome severity, Sequential Organ Failure Assessment scores, ICU and hospital mortality, and were less likely to be diagnosed with acute respiratory distress syndrome by clinicians. In adjusted analysis, spontaneous breathing during the first 2 days was not associated with an effect on ICU or hospital mortality (33% vs 37%; odds ratio, 1.18 [0.92-1.51]; p = 0.19 and 37% vs 41%; odds ratio, 1.18 [0.93-1.50]; p = 0.196, respectively ). Spontaneous breathing was associated with increased ventilator-free days (13 [0-22] vs 8 [0-20]; p = 0.014) and shorter duration of ICU stay (11 [6-20] vs 12 [7-22]; p = 0.04). CONCLUSIONS: Spontaneous breathing is common in patients with acute respiratory distress syndrome during the first 48 hours of mechanical ventilation. Spontaneous breathing is not associated with worse outcomes and may hasten liberation from the ventilator and from ICU. Although these results support the use of spontaneous breathing in patients with acute respiratory distress syndrome independent of acute respiratory distress syndrome severity, the use of controlled ventilation indicates a bias toward use in patients with higher disease severity. In addition, because the lack of reliable data on inspiratory effort in our study, prospective studies incorporating the magnitude of inspiratory effort and adjusting for all potential severity confounders are required

Epidemiology and patterns of tracheostomy practice in patients with acute respiratory distress syndrome in ICUs across 50 countries

Background: To better understand the epidemiology and patterns of tracheostomy practice for patients with acute respiratory distress syndrome (ARDS), we investigated the current usage of tracheostomy in patients with ARDS recruited into the Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG-SAFE) study. Methods: This is a secondary analysis of LUNG-SAFE, an international, multicenter, prospective cohort study of patients receiving invasive or noninvasive ventilation in 50 countries spanning 5 continents. The study was carried out over 4 weeks consecutively in the winter of 2014, and 459 ICUs participated. We evaluated the clinical characteristics, management and outcomes of patients that received tracheostomy, in the cohort of patients that developed ARDS on day 1-2 of acute hypoxemic respiratory failure, and in a subsequent propensity-matched cohort. Results: Of the 2377 patients with ARDS that fulfilled the inclusion criteria, 309 (13.0%) underwent tracheostomy during their ICU stay. Patients from high-income European countries (n = 198/1263) more frequently underwent tracheostomy compared to patients from non-European high-income countries (n = 63/649) or patients from middle-income countries (n = 48/465). Only 86/309 (27.8%) underwent tracheostomy on or before day 7, while the median timing of tracheostomy was 14 (Q1-Q3, 7-21) days after onset of ARDS. In the subsample matched by propensity score, ICU and hospital stay were longer in patients with tracheostomy. While patients with tracheostomy had the highest survival probability, there was no difference in 60-day or 90-day mortality in either the patient subgroup that survived for at least 5 days in ICU, or in the propensity-matched subsample. Conclusions: Most patients that receive tracheostomy do so after the first week of critical illness. Tracheostomy may prolong patient survival but does not reduce 60-day or 90-day mortality. Trial registration: ClinicalTrials.gov, NCT02010073. Registered on 12 December 2013

Effect of Rice Allelochemical, Mulch and Herbicides on Growth of Wheat under Different Crop Establishment Methods

In India wheat is grown mostly after rice in Rice-wheat system, which effects the establishment of wheat crop because field requirement of both crop is different so there is need of studying other better crop establishment methods for wheat. This experiment was carried out in research farm of Banaras Hindu University, Varanasi, Uttar Pradesh in split plot design with three replication, where three different crop establishment methods i.e. conventional method, raised bed and zero-till in main plot and in subplot five different weed control practices along with control (weedy check) allotted. From the observation it found that plant height of crop was significantly higher in zero-till plot than conventional and raised bed method. Among weed management practices rice residue as mulch @ 4 t ha-1 fb clodinofop propargyl + metsulfuron @ 100% of recommended dose ( 2-4 leaf stage of weed), Clodinofop propargyl @ 60g a.i. ha-1 + metsulfuron @ 4g a.i. ha-1 , Rice residue as mulch @ 4 t ha-1 fb rice extract (10gL-1) at 2-4 leaf stage of weed , two hand weeding at 20 and 40 DAS, Clodinofop propargyl @ 75% of recommended dose + rice extract (10gL-1) at 2-4 leaf stage of weed gave significantly higher plant height than weedy check plot. For higher yield, growth of crop must be enhanced so it’s better to go for zero-till sowing for wheat than conventional method

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Not AvailableSeed biomineralization is an important biochemical process by which the mature seeds reserve some of the essential macro and micronutrients required during germination. One of the most widely studied seed biomineralization process is the storage of seed phosphorous (P) and other important cations namely calcium (Ca), potassium (K), Magnesium (Mg), Manganese (Mn), Iron (Fe)and Zinc (Zn) in phytate or phytic acid (PA) salts. The seed biomineralization is provide essential micro- and macronutrients to germinating seeds through their mobilization; most the above mentioned mineral elements act as an important co factor in several metabolic processes; either directly or indirectly determine the function or efficiency of several enzymes which catalyze several biochemical processes. However, sometimes the level of such reserves in some of the crops like maize, soybean, barley, wheat and many other crops are so high that the level is not only well above the requirement by the germinating seeds but also affects the bioavailability of such nutrients in animals which depend on these crops for their dietary nutritional requirement. In this context, PA has been termed rightly as an anti-nutritional factor and it is an important challenge to reduce its level without compromising the overall germination and vigour of the seedlings in different crop species. The distribution of the phytate and other essential mineral elements in different parts of the seeds especially in cereals were studies (O’Dell et al. 1972). The results suggested that >80% of the total phosphorous is stored in the form of PA. The distribution of PA among different parts of the seeds has shown that approximately 8090% of the PA is stored in germ (maize) or pericarp (rice) or aleurone layer (wheat); differential storage organ depending upon the type of grain or crop. Raboy et al (1990) for the first time in maize surveyed the level of PA in different maize mutants. The study on different mutations has gave an opportunity to explore for breeding for low phytic acid in maize as the study has indicated that the mutants which affect the embryo reduced the PA substantially without reducing the total P; the corresponding increase in the inorganic phosphorous (Pi) was observed. In maize, several mutant alleles in three different gene(s) namely lpa1, lpa2and lpa3 which affect three important critical steps in PA biosynthesis namely PA transportation, insositol phosphate kinases (IPK) or myoinsositol kinases (MIK) have been identified (Raboy et al. 2000 and Shi et al. 2005). The first effort to transfer of LPA mutant lpa1-1 into different genetic background mainly the elite lines of hybrids was attempted as early as 1998. Several near-isogenic lines (NILs) by transferring lpa1-1 have been developed and isohybrids using such NILSs have also been developed. The performances of such resultant isohybrid were evaluated for various agronomic and different yield component traits across multiple locations. The results had shown that the hybrids have showed normal growth and development from germination to harvesting. The hybrids have shown good stalk strength/ standability and also comparable traits for flowering and other yield contributing traits. (Ertl et al. 1998, Raboy, 2002). In recent years, the availability of molecular markers linked to gene(s) determining low phytic acid traits has facilitated breeders to mobilize such mutant alleles across different genetic background through marker-assisted selection (MAS). In case of maize, few elite inbred lines are converted by transferring LPA mutants like lpa11 (Naidoo et al. 2012), lpa22 (Tamilkumar et al. 2014, Sureshkumar et al. 2014a, 2014b). However, the low phytic hybrids have as yet not released in India commercial cultivation. Presently in India, several hybrids are under pipeline with lowphytic acid mutant alleles which are at various developmental stages. The hybrids are being developed through marker assisted backcross breeding (MABB).Not Availabl